Method of treating C3 glomerulopathy

ABSTRACT

Methods of treating a human suffering from or susceptible to C3 glomerulopathy comprising administering to the human an effective amount of a C5aR antagonist are provided.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/184,535 filed Nov. 8, 2018, which application is a continuation ofU.S. patent application Ser. No. 15/404,610 filed Jan. 12, 2017(abandoned), which application claims priority benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 62/278,788 filed Jan. 14,2016; U.S. Provisional Application No. 62/280,346 filed Jan. 19, 2016;U.S. Provisional Application No. 62/347,450 filed Jun. 8, 2016; and U.S.Provisional Application No. 62/397,527 filed Sep. 21, 2016, each ofwhich is herein incorporated by reference in its entirety for allpurposes.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

Not Applicable

REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED ON A COMPACT DISK

Not Applicable

BACKGROUND OF THE INVENTION

C3 glomerulopathy (C3G) is a rare disease of the kidney (the prevalenceof C3G is estimated at 2-3 per 1,000,000 people). C3G is characterizedby deposition of the protein known as C3 (a component of the body'scomplement system) in the filtration units (the glomeruli) of thekidney, indicating complement involvement in causing kidney damage. C3glomerulopathy is characterized by evidence of alternative complementactivation based on C3 deposition in the glomeruli. There are two formsof the disease: dense deposit disease (DDD, formerly calledmembranoproliferative glomerulonephritis [MPGN] Type II) and C3glomerulonephritis (C3GN, formerly called idiopathic MPGN). Geneticlesions leading to defective complement regulation, including mutationsin complement factor H (CFH) have been described in these patients.Patients with C3 glomerulopathy often have high proteinuria andprogressive deterioration in renal function. There is no approvedtreatment for patients with C3 glomerulopathy, including C3GN. Withouttreatment, C3G invariably leads to kidney failure, and kidney transplantis frequently the only option. Even after transplantation, the newkidney will frequently fail due to recurrence of the disease.

BRIEF SUMMARY OF THE INVENTION

The present disclosure is directed to a method of treating a humansuffering from or susceptible to C3 glomerulopathy comprisingadministering to the human an effective amount of a C5aR antagonist.

In one embodiment, the C5aR antagonist is a compound having the formula(I), or a pharmaceutically acceptable salt thereof,

wherein

-   -   C¹ is phenyl optionally substituted with from 1 to 3 R¹        substituents;    -   C² is phenyl optionally substituted with from 1 to 3 R²        substituents;    -   C³ is selected from the group consisting of C₃₋₈ cycloalkyl and        phenyl, and each C³ is optionally substituted with from 1-3 R³        substituents;    -   each R¹ is independently selected from the group consisting of        -   halogen, —CN, —CO₂R^(a), —CONR^(a)R^(b), —C(O)R^(a),            —OC(O)NR^(a)R^(b), —NR^(b)C(O)R^(a), —NR^(b)C(O)₂R^(c),            —NR^(a)C(O)NR^(a)R^(b), —NR^(a)R^(b), —OR^(a), and            —S(O)₂NR^(a)R^(b); wherein each R^(a) and R^(b) is            independently selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈            haloalkyl, or when attached to the same nitrogen atom can be            combined with the nitrogen atom to form a five or            six-membered ring having from 0 to 2 additional heteroatoms            as ring members selected from N, O or S; each R^(c) is            independently selected from the group consisting of C₁₋₈            alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl, heterocycloalkyl,            aryl and heteroaryl, and wherein the aliphatic and cyclic            portions of R^(a), R^(b) and R^(c) are optionally further            substituted with from one to three halogen, hydroxy, methyl,            amino, alkylamino and dialkylamino groups; and optionally            when two R¹ substituents are on adjacent atoms, are combined            to form a fused five or six-membered carbocyclic ring;    -   each R² is independently selected from the group consisting of        -   halogen, —CN, —R^(f), —CO₂R^(d), —CONR^(d)R^(e), —C(O)R^(d),            —OC(O)NR^(d)R^(e), —NR^(e)C(O)R^(d), —NR^(e)C(O)₂R^(f),            —NR^(d)C(O)NR^(d)R^(e), —NR^(d)C(O)NR^(d)R^(e),            —NR^(d)R^(e), —OR^(d), and —S(O)₂NR^(d)R^(e); wherein each            R^(d) and R^(e) is independently selected from hydrogen,            C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached to the same            nitrogen atom can be combined with the nitrogen atom to form            a five or six-membered ring having from 0 to 2 additional            heteroatoms as ring members selected from N, O or S; each            R^(f) is independently selected from the group consisting of            C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,            heterocycloalkyl, aryl and heteroaryl, and wherein the            aliphatic and cyclic portions of R^(d), R^(e) and R^(f) are            optionally further substituted with from one to three            halogen, hydroxy, methyl, amino, alkylamino and dialkylamino            groups;    -   each R³ is independently selected from the group consisting of        -   halogen, —CN, —CO₂R^(g), —CONR^(g)R^(h), —C(O)R^(g),            —OC(O)NR^(g)R^(h), —NR^(h)C(O)R^(g), —NR^(h)C(O)₂R^(i),            —NR^(g)C(O)NR^(g)R^(h), —NR^(g)R^(h), —OR^(g),            —S(O)₂NR^(g)R^(h), —X⁴—R^(j), —X⁴—NR^(g)R^(h),            —X⁴—CONR^(g)R^(h), —X⁴—NR^(h)C(O)R^(g), —NHR^(j) and            —NHCH₂R^(j), wherein X⁴ is a C₁₋₄ alkylene; each R^(g) and            R^(h) is independently selected from hydrogen, C₁₋₈ alkyl,            C₃₋₆ cycloalkyl and C₁₋₈haloalkyl, or when attached to the            same nitrogen atom can be combined with the nitrogen atom to            form a five or six-membered ring having from 0 to 2            additional heteroatoms as ring members selected from N, O or            S and is optionally substituted with one or two oxo; each            R^(i) is independently selected from the group consisting of            C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,            heterocycloalkyl, aryl and heteroaryl; and each is selected            from the group consisting of C₃₋₆ cycloalkyl, pyrrolinyl,            piperidinyl, morpholinyl, tetrahydrofuranyl, and            tetrahydropyranyl, and wherein the aliphatic and cyclic            portions of R^(g), R^(h), R^(i) and R^(j) are optionally            further substituted with from one to three halogen, methyl,            CF₃, hydroxy, amino, alkylamino and dialkylamino groups; and    -   X is hydrogen or CH₃.

In some embodiments, the C5aR antagonist is a compound having theformula:

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 represents the patient's Estimated glomerular filtration rate(eGFR) before and after treatment with compound 1.

FIG. 2 represents the histopathological improvement following treatmentwith compound 1.

DETAILED DESCRIPTION OF THE INVENTION Abbreviation and Definitions

The term “alkyl”, by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain hydrocarbonradical, having the number of carbon atoms designated (i.e. C₁₋₈ meansone to eight carbons). Examples of alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. The term “alkenyl” refers toan unsaturated alkyl group having one or more double bonds. Similarly,the term “alkynyl” refers to an unsaturated alkyl group having one ormore triple bonds. Examples of such unsaturated alkyl groups includevinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers. The term “cycloalkyl”refers to hydrocarbon rings having the indicated number of ring atoms(e.g., C₃₋₆cycloalkyl) and being fully saturated or having no more thanone double bond between ring vertices. “Cycloalkyl” is also meant torefer to bicyclic and polycyclic hydrocarbon rings such as, for example,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. The term“heterocycloalkyl” refers to a cycloalkyl group that contain from one tofive heteroatoms selected from N, O, and S, wherein the nitrogen andsulfur atoms are optionally oxidized, and the nitrogen atom(s) areoptionally quaternized. The heterocycloalkyl may be a monocyclic, abicyclic or a polycyclic ring system. Non limiting examples ofheterocycloalkyl groups include pyrrolidine, imidazolidine,pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin,dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine,thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide,piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone,tetrahydrofuran, tetrahydrothiophene, quinuclidine, and the like. Aheterocycloalkyl group can be attached to the remainder of the moleculethrough a ring carbon or a heteroatom.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified by—CH₂CH₂CH₂CH₂—. Typically, an alkyl (or alkylene) group will have from 1to 24 carbon atoms, with those groups having 10 or fewer carbon atomsbeing preferred in the present disclosure. A “lower alkyl” or “loweralkylene” is a shorter chain alkyl or alkylene group, generally havingfour or fewer carbon atoms. Similarly, “alkenylene” and “alkynylene”refer to the unsaturated forms of “alkylene” having double or triplebonds, respectively.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting of thestated number of carbon atoms and from one to three heteroatoms selectedfrom the group consisting of O, N, Si and S, and wherein the nitrogenand sulfur atoms may optionally be oxidized and the nitrogen heteroatommay optionally be quaternized. The heteroatom(s) O, N and S may beplaced at any interior position of the heteroalkyl group. The heteroatomSi may be placed at any position of the heteroalkyl group, including theposition at which the alkyl group is attached to the remainder of themolecule. Examples include —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. Similarly, the terms“heteroalkenyl” and “heteroalkynyl” by itself or in combination withanother term, means, unless otherwise stated, an alkenyl group oralkynyl group, respectively, that contains the stated number of carbonsand having from one to three heteroatoms selected from the groupconsisting of O, N, Si and S, and wherein the nitrogen and sulfur atomsmay optionally be oxidized and the nitrogen heteroatom may optionally bequaternized. The heteroatom(s) O, N and S may be placed at any interiorposition of the heteroalkyl group.

The term “heteroalkylene” by itself or as part of another substituentmeans a divalent radical, saturated or unsaturated or polyunsaturated,derived from heteroalkyl, as exemplified by —CH₂—CH₂—S—CH₂CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—, —O—CH₂—CH═CH—, —CH₂—CH═C(H)CH₂—O—CH₂— and—S—CH₂—C≡C—. For heteroalkylene groups, heteroatoms can also occupyeither or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy,alkyleneamino, alkylenediamino, and the like).

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively. Additionally, for dialkylaminogroups, the alkyl portions can be the same or different and can also becombined to form a 3-7 membered ring with the nitrogen atom to whicheach is attached. Accordingly, a group represented as —NR^(a)R^(b) ismeant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl andthe like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“C₁₋₄ haloalkyl” is mean to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,typically aromatic, hydrocarbon group which can be a single ring ormultiple rings (up to three rings) which are fused together or linkedcovalently. The term “heteroaryl” refers to aryl groups (or rings) thatcontain from one to five heteroatoms selected from N, O, and S, whereinthe nitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. A heteroaryl group can be attachedto the remainder of the molecule through a heteroatom. Non-limitingexamples of aryl groups include phenyl, naphthyl and biphenyl, whilenon-limiting examples of heteroaryl groups include pyridyl, pyridazinyl,pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl,quinazolinyl, cinnolinyl, phthalaziniyl, benzotriazinyl, purinyl,benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl,isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl,thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines,benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl,isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl,thiazolyl, furyl, thienyl and the like. Substituents for each of theabove noted aryl and heteroaryl ring systems are selected from the groupof acceptable substituents described below.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the term “arylalkyl” is meant to includethose radicals in which an aryl group is attached to an alkyl group(e.g., benzyl, phenethyl, pyridylmethyl and the like).

The above terms (e.g., “alkyl,” “aryl” and “heteroaryl”), in someembodiments, will include both substituted and unsubstituted forms ofthe indicated radical. Preferred substituents for each type of radicalare provided below. For brevity, the terms aryl and heteroaryl willrefer to substituted or unsubstituted versions as provided below, whilethe term “alkyl” and related aliphatic radicals is meant to refer tounsubstituted version, unless indicated to be substituted.

Substituents for the alkyl radicals (including those groups oftenreferred to as alkylene, alkenyl, alkynyl and cycloalkyl) can be avariety of groups selected from: -halogen, —OR′, —NR′R″, —SR′,—SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR′S(O)₂R″, —CN and—NO₂ in a number ranging from zero to (2 m′+1), where m′ is the totalnumber of carbon atoms in such radical. R′, R″ and R′″ eachindependently refer to hydrogen, unsubstituted C₁₋₈ alkyl, unsubstitutedheteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens,unsubstituted C₁₋₈ alkyl, C₁₋₈ alkoxy or C₁₋₈ thioalkoxy groups, orunsubstituted aryl-C₁₋₄ alkyl groups. When R′ and R″ are attached to thesame nitrogen atom, they can be combined with the nitrogen atom to forma 3-, 4-, 5-, 6-, or 7-membered ring. For example, —NR′R″ is meant toinclude 1-pyrrolidinyl and 4-morpholinyl. The term “acyl” as used byitself or as part of another group refers to an alkyl radical whereintwo substitutents on the carbon that is closest to the point ofattachment for the radical is replaced with the substitutent ═O (e.g.,—C(O)CH₃, —C(O)CH₂CH₂OR′ and the like).

Similarly, substituents for the aryl and heteroaryl groups are variedand are generally selected from: -halogen, —OR′, —OC(O)R′, —NR′R″, —SR′,—R′, —CN, —NO₂, —CO₂R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′,—NR″C(O)₂R′, —NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR′S(O)₂R″, —N₃,perfluoro(C₁-C₄)alkoxy, and perfluoro(C₁-C₄)alkyl, in a number rangingfrom zero to the total number of open valences on the aromatic ringsystem; and where R′, R″ and R′″ are independently selected fromhydrogen, C₁₋₈ alkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C₁₋₄ alkyl, andunsubstituted aryloxy-C₁₋₄ alkyl. Other suitable substituents includeeach of the above aryl substituents attached to a ring atom by analkylene tether of from 1-4 carbon atoms.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula—T—C(O)—(CH₂)_(q)—U—, wherein T and U are independently —NH—, —O—, —CH₂—or a single bond, and q is an integer of from 0 to 2.

Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula -A-(CH₂)_(r)—B—, wherein A and B are independently —CH₂—, —O—,—NH—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′ or a single bond, and r is aninteger of from 1 to 3. One of the single bonds of the new ring soformed may optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituent R′ in —NR′— and —S(O)₂NR′— is selected from hydrogen orunsubstituted C₁₋₆ alkyl.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), sulfur (S) and silicon (Si).

The term “ionic liquid” refers to any liquid that contains mostly ions.Preferably, in the present disclosure, “ionic liquid” refers to thesalts whose melting point is relatively low (e.g., below 250° C.).Examples of ionic liquids include but are not limited to1-butyl-3-methylimidazolium tetrafluoroborate,1-hexyl-3-methylimidazolium tetrafluoroborate,1-octyl-3-methylimidazolium tetrafluoroborate,1-nonyl-3-methylimidazolium tetrafluoroborate,1-decyl-3-methylimidazolium tetrafluoroborate,1-hexyl-3-methylimidazolium hexafluorophosphate and1-hexyl-3-methylimidazolium bromide, and the like.

As used herein, the term “treating” or “treatment” encompasses bothdisease-modifying treatment and symptomatic treatment, either of whichmay be prophylactic (i.e., before the onset of symptoms, in order toprevent, delay or reduce the severity of symptoms) or therapeutic (i.e.,after the onset of symptoms, in order to reduce the severity and/orduration of symptoms). Treatment methods provided herein include, ingeneral, administration to a patient an effective amount of one or morecompounds provided herein. Suitable patients include those patientssuffering from or susceptible to {i.e., prophylactic treatment) adisorder or disease identified herein. Typical patients for treatment asdescribed herein include mammals, particularly primates, especiallyhumans. Other suitable patients include domesticated companion animalssuch as a dog, cat, horse, and the like, or a livestock animal such ascattle, pig, sheep and the like.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present disclosurecontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of salts derived frompharmaceutically-acceptable inorganic bases include aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,manganous, potassium, sodium, zinc and the like. Salts derived frompharmaceutically-acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occurring amines and the like, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperadine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. When compounds of the presentdisclosure contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, malonic, benzoic, succinic, suberic,fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, for example,Berge, S. M., et al, “Pharmaceutical Salts”, Journal of PharmaceuticalScience, 1977, 66, 1-19). Certain specific compounds of the presentdisclosure contain both basic and acidic functionalities that allow thecompounds to be converted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present disclosure.

The compounds described in the Embodiments below can be obtainedaccording to methods described in WO 2010/075257, WO 2011/163640 and WO2016/053890.

EMBODIMENTS

The present disclosure is directed to a method of treating a humansuffering from or susceptible to complement 3 glomerulopathy comprisingadministering to the human an effective amount of a compound having theformula (I), or a pharmaceutically acceptable salt thereof,

wherein

-   -   C¹ is phenyl optionally substituted with from 1 to 3 R¹        substituents;    -   C² is phenyl optionally substituted with from 1 to 3 R²        substituents;    -   C³ is selected from the group consisting of C₃₋₈ cycloalkyl and        phenyl, and each C³ is optionally substituted with from 1-3 R³        substituents;    -   each R¹ is independently selected from the group consisting of        -   halogen, —CN, —R^(c), —CO₂R^(a), —CONR^(a)R^(b), —C(O)R^(a),            —OC(O)NR^(a)R^(b), —NR^(b)C(O)R^(a), —NR^(b)C(O)₂R^(c),            —NR^(a)C(O)NR^(a)R^(b), —OR^(a), and —S(O)₂NR^(a)R^(b);            wherein each R^(a) and R^(b) is independently selected from            hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached            to the same nitrogen atom can be combined with the nitrogen            atom to form a five or six-membered ring having from 0 to 2            additional heteroatoms as ring members selected from N, O or            S; each R^(c) is independently selected from the group            consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,            heterocycloalkyl, aryl and heteroaryl, and wherein the            aliphatic and cyclic portions of R^(a), R^(b) and R^(c) are            optionally further substituted with from one to three            halogen, hydroxy, methyl, amino, alkylamino and dialkylamino            groups; and optionally when two R¹ substituents are on            adjacent atoms, are combined to form a fused five or            six-membered carbocyclic ring;    -   each R² is independently selected from the group consisting of        -   halogen, —CN, —R^(f), —CO₂R^(d), —CONR^(d)R^(e), —C(O)R^(d),            —OC(O)NR^(d)R^(e), —NR^(e)C(O)R^(d), —NR^(e)C(O)₂R^(f),            —NR^(d)C(O)NR^(d)R^(e), —NR^(d)C(O)NR^(d)R^(e),            —NR^(d)R^(e), —OR^(d), and —S(O)₂NR^(d)R^(e); wherein each            R^(d) and R^(e) is independently selected from hydrogen,            C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached to the same            nitrogen atom can be combined with the nitrogen atom to form            a five or six-membered ring having from 0 to 2 additional            heteroatoms as ring members selected from N, O or S; each            R^(f) is independently selected from the group consisting of            C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,            heterocycloalkyl, aryl and heteroaryl, and wherein the            aliphatic and cyclic portions of R^(d), R^(e) and R^(f) are            optionally further substituted with from one to three            halogen, hydroxy, methyl, amino, alkylamino and dialkylamino            groups;    -   each R³ is independently selected from the group consisting of        -   halogen, —CN, —R^(i), —CO₂R^(g), —CONR^(g)R^(h), —C(O)R^(g),            —OC(O)NR^(g)R^(h), —NR^(h)C(O)R^(g), —NR^(h)C(O)₂R^(i),            —NR^(g)C(O)NR^(g)R^(h), —NR^(g)R^(h), —OR^(g),            —S(O)₂NR^(g)R^(h), —X⁴—R^(j), —X⁴—NR^(g)R^(h),            —X⁴—CONR^(g)R^(h), —X⁴—NR^(h)C(O)R^(g), —NHR^(j) and            —NHCH₂R^(j), wherein X⁴ is a C₁₋₄ alkylene; each R^(g) and            R^(h) is independently selected from hydrogen, C₁₋₈ alkyl,            C₃₋₆ cycloalkyl and C₁₋₈ haloalkyl, or when attached to the            same nitrogen atom can be combined with the nitrogen atom to            form a five or six-membered ring having from 0 to 2            additional heteroatoms as ring members selected from N, O or            S and is optionally substituted with one or two oxo; each            R^(i) is independently selected from the group consisting of            C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,            heterocycloalkyl, aryl and heteroaryl; and each R^(j) is            selected from the group consisting of C₃₋₆ cycloalkyl,            pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and            tetrahydropyranyl, and wherein the aliphatic and cyclic            portions of R^(g), R^(h), R^(i) and R^(j) are optionally            further substituted with from one to three halogen, methyl,            CF₃, hydroxy, amino, alkylamino and dialkylamino groups; and    -   X is hydrogen or CH₃.

In some embodiments, the compound has the formula (Ia):

In some embodiments, the compound has the formula (Ib):

Ib

wherein

-   -   X¹ is selected from the group consisting of CH and CR¹;    -   the subscript n is an integer of from 0 to 2;    -   X² is selected from the group consisting of CH and CR²; and    -   the subscript m is an integer of from 0 to 2.

In some embodiments, the compound has the formula (Ic):

wherein

-   -   X¹ is selected from the group consisting of CH and CR¹;    -   the subscript n is an integer of from 0 to 2;    -   X² is selected from the group consisting of CH and CR²; and    -   the subscript m is an integer of from 0 to 2.

In some embodiments, the compound has the formula (Id):

wherein

-   -   the subscript p is an integer of from 0 to 3;    -   X¹ is selected from the group consisting of CH and CR¹;    -   the subscript n is an integer of from 0 to 2;    -   X² is selected from the group consisting of CH and CR²; and    -   the subscript m is an integer of from 0 to 2.

In some embodiments, the compound has the formula (Ie):

wherein p is 0, 1 or 2.

In some embodiments, the compound is selected from the group consistingof

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

A method of slowing the rate of decline in Estimated GlomerularFiltration Rate (eGFR) in a human suffering from or susceptible to C3glomerulopathy is provided comprising administering to the human aneffective amount of a compound having the formula (I), or apharmaceutically acceptable salt thereof,

wherein

-   -   C¹ is phenyl optionally substituted with from 1 to 3 R¹        substituents;    -   C² is phenyl optionally substituted with from 1 to 3 R²        substituents;    -   C³ is selected from the group consisting of C₃₋₈ cycloalkyl and        phenyl, and each C³ is optionally substituted with from 1-3 R³        substituents;    -   each R¹ is independently selected from the group consisting of        -   halogen, —CN, —R^(c), —CO₂R^(a), —CONR^(a)R^(b), —C(O)R^(a),            —OC(O)NR^(a)R^(b), —NR^(b)C(O)R^(a), —NR^(b)C(O)₂R^(c),            —NR^(a)C(O)NR^(a)R^(b), —OR¹, and —S(O)₂NR^(a)R^(b); wherein            each R^(a) and R^(b) is independently selected from            hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached            to the same nitrogen atom can be combined with the nitrogen            atom to form a five or six-membered ring having from 0 to 2            additional heteroatoms as ring members selected from N, O or            S; each R^(c) is independently selected from the group            consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,            heterocycloalkyl, aryl and heteroaryl, and wherein the            aliphatic and cyclic portions of R^(a), R^(b) and R^(c) are            optionally further substituted with from one to three            halogen, hydroxy, methyl, amino, alkylamino and dialkylamino            groups; and optionally when two R¹ substituents are on            adjacent atoms, are combined to form a fused five or            six-membered carbocyclic ring;    -   each R² is independently selected from the group consisting of        -   halogen, —CN, —R^(f), —CO₂R^(d), —CONR^(d)R^(e), —C(O)R^(d),            —OC(O)NR^(d)R^(e), —NR^(e)C(O)R^(d), —NR^(e)C(O)₂R^(f),            —NR^(d)C(O)NR^(d)R^(e), —NR^(d)C(O)NR^(d)R^(e),            —NR^(d)R^(e), —OR^(d), and —S(O)₂NR^(d)R^(e); wherein each            R^(d) and R^(e) is independently selected from hydrogen,            C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached to the same            nitrogen atom can be combined with the nitrogen atom to form            a five or six-membered ring having from 0 to 2 additional            heteroatoms as ring members selected from N, O or S; each            R^(f) is independently selected from the group consisting of            C₁₋₈ alkyl, C₁₋₈ haloalkyl, C3-6 cycloalkyl,            heterocycloalkyl, aryl and heteroaryl, and wherein the            aliphatic and cyclic portions of R^(d), R^(e) and R^(f) are            optionally further substituted with from one to three            halogen, hydroxy, methyl, amino, alkylamino and dialkylamino            groups;    -   each R³ is independently selected from the group consisting of        -   halogen, —CN, —R^(i), —CO₂R^(g), —CONR^(g)R^(h), —C(O)R^(g),            —OC(O)NR^(g)R^(h), —NR^(h)C(O)R^(g), —NR^(h)C(O)₂R^(i),            —NR^(g)C(O)NR^(g)R^(h), —NR^(g)R^(h), —OR^(g),            —S(O)₂NR^(g)R^(h), —X⁴—R^(j), —X⁴—NR^(g)R^(h),            —X⁴—CONR^(g)R^(h), —X⁴—NR^(h)C(O)R^(g), —NHR^(j) and            —NHCH₂R^(j), wherein X⁴ is a C₁₋₄ alkylene; each R^(g) and            R^(h) is independently selected from hydrogen, C₁₋₈ alkyl,            C₃₋₆ cycloalkyl and C₁₋₈haloalkyl, or when attached to the            same nitrogen atom can be combined with the nitrogen atom to            form a five or six-membered ring having from 0 to 2            additional heteroatoms as ring members selected from N, O or            S and is optionally substituted with one or two oxo; each            R^(i) is independently selected from the group consisting of            C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,            heterocycloalkyl, aryl and heteroaryl; and each R^(j) is            selected from the group consisting of C₃₋₆ cycloalkyl,            pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and            tetrahydropyranyl, and wherein the aliphatic and cyclic            portions of R^(g), R^(h), R^(i) and R^(j) are optionally            further substituted with from one to three halogen, methyl,            CF₃, hydroxy, amino, alkylamino and dialkylamino groups; and    -   X is hydrogen or CH₃.

In some embodiments, the compound has the formula (Ie):

wherein p is 0, 1 or 2.

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

A method of reducing glomerular inflammation in a human suffering fromor susceptible to C3 glomerulopathy is provided comprising administeringto the human an effective amount of a compound having the formula (I),or a pharmaceutically acceptable salt thereof,

wherein

-   -   C¹ is phenyl optionally substituted with from 1 to 3 R¹        substituents;    -   C² is phenyl optionally substituted with from 1 to 3 R²        substituents;    -   C³ is selected from the group consisting of C₃₋₈ cycloalkyl and        phenyl, and each C³ is optionally substituted with from 1-3 R³        substituents;    -   each R¹ is independently selected from the group consisting of        -   halogen, —CN, —R^(c), —CO₂R^(a), —CONR^(a)R^(b), —C(O)R^(a),            —OC(O)NR^(a)R^(b), —NR^(b)C(O)R^(a), —NR^(b)C(O)₂R^(c),            —NR^(a)C(O)NR^(a)R^(b), —OR^(a), and —S(O)₂NR^(a)R^(b);            where in each R^(a) and R^(b) is independently selected from            hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached            to the same nitrogen atom can be combined with the nitrogen            atom to form a five or six-membered ring having from 0 to 2            additional heteroatoms as ring members selected from N, O or            S; each R^(c) is independently selected from the group            consisting of C₁₋₈ alkyl, C₁₋₈haloalkyl, C₃₋₆ cycloalkyl,            heterocycloalkyl, aryl and heteroaryl, and wherein the            aliphatic and cyclic portions of R^(a), R^(b) and R^(c) are            optionally further substituted with from one to three            halogen, hydroxy, methyl, amino, alkylamino and dialkylamino            groups; and optionally when two R¹ substituents are on            adjacent atoms, are combined to form a fused five or            six-membered carbocyclic ring;    -   each R² is independently selected from the group consisting of        -   halogen, —CN, —R^(f), —CO₂R^(d), —CONR^(d)R^(e), —C(O)R^(d),            —OC(O)NR^(d)R^(e), —NR^(e)C(O)R^(d), —NR^(e)C(O)₂R^(f),            —NR^(d)C(O)NR^(d)R^(e), —NR^(d)C(O)NR^(d)R^(e),            —NR^(d)R^(e), —OR^(d), and —S(O)₂NR^(d)R^(e); wherein each            R^(d) and R^(e) is independently selected from hydrogen,            C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached to the same            nitrogen atom can be combined with the nitrogen atom to form            a five or six-membered ring having from 0 to 2 additional            heteroatoms as ring members selected from N, O or S; each            R^(f) is independently selected from the group consisting of            C₁₋₈ alkyl, C₁₋₈haloalkyl, C₃₋₆ cycloalkyl,            heterocycloalkyl, aryl and heteroaryl, and wherein the            aliphatic and cyclic portions of R^(d), R^(e) and R^(f) are            optionally further substituted with from one to three            halogen, hydroxy, methyl, amino, alkylamino and dialkylamino            groups;    -   each R³ is independently selected from the group consisting of        -   halogen, —CN, —R^(i), —CO₂R^(g), —CONR^(g)R^(h), —C(O)R^(g),            —OC(O)NR^(g)R^(h), —NR^(h)C(O)R^(g), —NR^(h)C(O)₂R^(i),            —NR^(g)C(O)NR^(g)R^(h), —NR^(g)R^(h), —OR^(g),            —S(O)₂NR^(g)R^(h), —X⁴—R^(j), —C⁴—NR^(g)R^(h),            —X⁴—CONR^(g)R^(h), —X⁴—NR^(h)C(O)R^(g), —NHR^(j) and            —NHCH₂R^(j), wherein X⁴ is a C₁₋₄ alkylene; each R^(g) and            R^(h) is independently selected from hydrogen, C₁₋₈ alkyl,            C₃₋₆ cycloalkyl and C₁₋₈ haloalkyl, or when attached to the            same nitrogen atom can be combined with the nitrogen atom to            form a five or six-membered ring having from 0 to 2            additional heteroatoms as ring members selected from N, O or            S and is optionally substituted with one or two oxo; each            R^(i) is independently selected from the group consisting of            C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,            heterocycloalkyl, aryl and heteroaryl; and each is selected            from the group consisting of C₃₋₆ cycloalkyl, pyrrolinyl,            piperidinyl, morpholinyl, tetrahydrofuranyl, and            tetrahydropyranyl, and wherein the aliphatic and cyclic            portions of R^(g), R^(h), R^(i) and R^(j) are optionally            further substituted with from one to three halogen, methyl,            CF₃, hydroxy, amino, alkylamino and dialkylamino groups; and    -   X is hydrogen or CH₃.

In some embodiments, the compound has the formula (Ie):

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

A method of reducing C3 deposits and/or C5b-9 deposits in a humansuffering from or susceptible to C3 glomerulopathy is providedcomprising administering to the human an effective amount of a compoundhaving the formula (I), or a pharmaceutically acceptable salt thereof,

wherein

-   -   C¹ is phenyl optionally substituted with from 1 to 3 R¹        substituents;    -   C² is phenyl optionally substituted with from 1 to 3 R²        substituents;    -   C³ is selected from the group consisting of C₃₋₈ cycloalkyl and        phenyl, and each C³ is optionally substituted with from 1-3 R³        substituents;    -   each R¹ is independently selected from the group consisting of        -   halogen, —CN, —R^(c), —CO₂R^(a), —CONR^(a)R^(b), —C(O)R^(a),            —OC(O)NR^(a)R^(b), —NR^(b)C(O)R^(a), —NR^(b)C(O)₂R^(c),            —NR^(a)C(O)NR^(a)R^(b), —OR^(a), and —S(O)₂NR^(a)R^(b);            wherein each R^(a) and R^(b) is independently selected from            hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached            to the same nitrogen atom can be combined with the nitrogen            atom to form a five or six-membered ring having from 0 to 2            additional heteroatoms as ring members selected from N, O or            S; each R^(c) is independently selected from the group            consisting of C₁₋₈ alkyl, C₁₋₈haloalkyl, C₃₋₆ cycloalkyl,            heterocycloalkyl, aryl and heteroaryl, and wherein the            aliphatic and cyclic portions of R^(a), R^(b) and R^(c) are            optionally further substituted with from one to three            halogen, hydroxy, methyl, amino, alkylamino and dialkylamino            groups; and optionally when two R¹ substituents are on            adjacent atoms, are combined to form a fused five or            six-membered carbocyclic ring;    -   each R² is independently selected from the group consisting of        -   halogen, —CN, —R^(f), —CO₂R^(d), —CONR^(d)R^(e), —C(O)R^(d),            —OC(O)NR^(d)R^(e), —NR^(e)C(O)R^(d), —NR^(e)C(O)₂R^(f),            —NR^(d)C(O)NR^(d)R^(e), —NR^(d)C(O)NR^(d)R^(e), —OR^(d), and            —S(O)₂NR^(d)R^(e); wherein each R^(d) and R^(e) is            independently selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈            haloalkyl, or when attached to the same nitrogen atom can be            combined with the nitrogen atom to form a five or            six-membered ring having from 0 to 2 additional heteroatoms            as ring members selected from N, O or S; each R^(f) is            independently selected from the group consisting of C₁₋₈            alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl, heterocycloalkyl,            aryl and heteroaryl, and wherein the aliphatic and cyclic            portions of R^(d), R^(e) and R^(f) are optionally further            substituted with from one to three halogen, hydroxy, methyl,            amino, alkylamino and dialkylamino groups;    -   each R³ is independently selected from the group consisting of        -   halogen, —CN, —R^(i), —CO₂R^(g), —CONR_(g)R^(h), —C(O)R^(g),            —OC(O)NR^(g)R^(h), —NR^(h)C(O)R^(g), —NR^(h)C(O)₂R^(i),            —NR^(g)C(O)NR^(g)R^(h), —NR^(g)R^(h), —OR^(g),            —S(O)₂NR^(g)R^(h), —X⁴—R^(j), —X⁴—NR^(g)R^(h),            —X⁴—CONR^(g)T^(h), —X⁴—NR^(h)C(O)R^(g), —NHR^(j) and            —NHCH₂R^(j), wherein X⁴ is a C₁₋₄ alkylene; each R^(g) and            R^(h) is independently selected from hydrogen, C₁₋₈ alkyl,            C₃₋₆ cycloalkyl and C₁₋₈ haloalkyl, or when attached to the            same nitrogen atom can be combined with the nitrogen atom to            form a five or six-membered ring having from 0 to 2            additional heteroatoms as ring members selected from N, O or            S and is optionally substituted with one or two oxo; each            R^(i) is independently selected from the group consisting of            C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,            heterocycloalkyl, aryl and heteroaryl; and each R^(j) is            selected from the group consisting of C₃₋₆ cycloalkyl,            pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and            tetrahydropyranyl, and wherein the aliphatic and cyclic            portions of R^(g), R^(h), R^(i) and R^(j) are optionally            further substituted with from one to three halogen, methyl,            CF₃, hydroxy, amino, alkylamino and dialkylamino groups; and    -   X is hydrogen or CH₃.

In some embodiments, the compound has the formula (Ie):

wherein p is 0, 1 or 2.

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the human suffers from complement 3glomerulonephritis. In some embodiments, the human suffers fromprogressive complement 3 glomerulonephritis. In some embodiments, thehuman suffers from recurrent complement 3 glomerulonephritis after arenal transplant. In some embodiments, the human suffers from densedeposit disease.

A method of clearing glomerular endocapillary proliferation in a humansuffering from or susceptible to C3 glomerulopathy is providedcomprising administering to the human an effective amount of a compoundhaving the formula (I), or a pharmaceutically acceptable salt thereof,

wherein

-   -   C¹ is phenyl optionally substituted with from 1 to 3 R¹        substituents;    -   C² is phenyl optionally substituted with from 1 to 3 R²        substituents;    -   C³ is selected from the group consisting of C₃₋₈ cycloalkyl and        phenyl, and each C³ is optionally substituted with from 1-3 R³        substituents;    -   each R¹ is independently selected from the group consisting of        -   halogen, —CN, —R^(c), —CO₂R^(a), —CONR^(a)R^(b), —C(O)R^(a),            —OC(O)NR^(a)R^(b), —NR^(b)C(O)R^(a), —NR^(b)C(O)₂R^(c),            —NR^(a)C(O)NR^(a)R^(b), —OR^(a), and —S(O)₂NR^(a)R^(b);            wherein each R^(a) and R^(b) is independently selected from            hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached            to the same nitrogen atom can be combined with the nitrogen            atom to form a five or six-membered ring having from 0 to 2            additional heteroatoms as ring members selected from N, O or            S; each R^(c) is independently selected from the group            consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,            heterocycloalkyl, aryl and heteroaryl, and wherein the            aliphatic and cyclic portions of R^(a), R^(b) and R^(c) are            optionally further substituted with from one to three            halogen, hydroxy, methyl, amino, alkylamino and dialkylamino            groups; and optionally when two R¹ substituents are on            adjacent atoms, are combined to form a fused five or            six-membered carbocyclic ring;    -   each R² is independently selected from the group consisting of        -   halogen, —CN, —R^(f), —CO₂R^(d), —CONR^(d)R^(e), —C(O)R^(d),            —OC(O)NR^(d)R^(e), —NR^(e)C(O)R^(d), —NR^(e)C(O)₂R^(f),            —NR^(d)C(O)NR^(d)R^(e), —NR^(d)C(O)NR^(d)R^(e),            —NR^(d)R^(e), —OR^(d), and —S(O)₂NR^(d)R^(e); wherein each            R^(d) and R^(e) is independently selected from hydrogen,            C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached to the same            nitrogen atom can be combined with the nitrogen atom to form            a five or six-membered ring having from 0 to 2 additional            heteroatoms as ring members selected from N, O or S; each            R^(f) is independently selected from the group consisting of            C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,            heterocycloalkyl, aryl and heteroaryl, and wherein the            aliphatic and cyclic portions of R^(d), R^(e) and R^(f) are            optionally further substituted with from one to three            halogen, hydroxy, methyl, amino, alkylamino and dialkylamino            groups;    -   each R³ is independently selected from the group consisting of        -   halogen, —CN, —R^(i), —CO₂R^(g), —CONR^(g)R^(h), —C(O)R^(g),            —OC(O)NR^(g)R^(h), —NR^(h)C(O)R^(g), —NR^(h)C(O)₂R^(i),            —NR^(g)C(O)NR^(g)R^(h), —NR^(g)R^(h), —OR^(g),            —S(O)₂NR^(g)R^(h), —X⁴—R^(j), —X⁴—NR^(g)R^(h),            —X⁴—CONR^(g)R^(h), —X⁴—NR^(h)C(O)R^(g), —NHR^(j) and            —NHCH₂R^(j), wherein X⁴ is a C₁₋₄ alkylene; each R^(g) and            R^(h) is independently selected from hydrogen, C₁₋₈ alkyl,            C₃₋₆ cycloalkyl and C₁₋₈ haloalkyl, or when attached to the            same nitrogen atom can be combined with the nitrogen atom to            form a five or six-membered ring having from 0 to 2            additional heteroatoms as ring members selected from N, O or            S and is optionally substituted with one or two oxo; each            R^(i) is independently selected from the group consisting of            C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,            heterocycloalkyl, aryl and heteroaryl; and each is selected            from the group consisting of C₃₋₆ cycloalkyl, pyrrolinyl,            piperidinyl, morpholinyl, tetrahydrofuranyl, and            tetrahydropyranyl, and wherein the aliphatic and cyclic            portions of R^(g), R^(h), R^(i) and R^(j) are optionally            further substituted with from one to three halogen, methyl,            CF₃, hydroxy, amino, alkylamino and dialkylamino groups; and    -   X is hydrogen or CH₃.

In some embodiments, the compound has the formula (Ie):

wherein p is 0, 1 or 2.

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

A method of reducing glomerular inflammatory macrophages in a humansuffering from or susceptible to C3 glomerulopathy is providedcomprising administering to the human an effective amount of a compoundhaving the formula (I), or a pharmaceutically acceptable salt thereof,

wherein

-   -   C¹ is phenyl optionally substituted with from 1 to 3 R¹        substituents;    -   C² is phenyl optionally substituted with from 1 to 3 R²        substituents;    -   C³ is selected from the group consisting of C₃₋₈ cycloalkyl and        phenyl, and each C³ is optionally substituted with from 1-3 R³        substituents;    -   each R¹ is independently selected from the group consisting of        -   halogen, —CN, —R^(c), —CO₂R^(a), —CONR^(a)R^(b), —C(O)R^(a),            —OC(O)NR^(a)R^(b), —NR^(b)C(O)R^(a), —NR^(b)C(O)₂R^(c),            —NR^(a)C(O)NR^(a)R^(b), —OR^(a), and —S(O)₂NR^(a)R^(b);            wherein each R^(a) and R^(b) is independently selected from            hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached            to the same nitrogen atom can be combined with the nitrogen            atom to form a five or six-membered ring having from 0 to 2            additional heteroatoms as ring members selected from N, O or            S; each R^(c) is independently selected from the group            consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,            heterocycloalkyl, aryl and heteroaryl, and wherein the            aliphatic and cyclic portions of R^(a), R^(b) and R^(c) are            optionally further substituted with from one to three            halogen, hydroxy, methyl, amino, alkylamino and dialkylamino            groups; and optionally when two R¹ substituents are on            adjacent atoms, are combined to form a fused five or            six-membered carbocyclic ring;    -   each R² is independently selected from the group consisting of        -   halogen, —CN, —R^(f), —CO₂R^(d), —CONR^(d)R^(e), —C(O)R^(d),            —OC(O)NR^(d)R^(e), —NR^(e)C(O)R^(d), —NR^(e)C(O)₂R^(f),            —NR^(d)C(O)NR^(d)R^(e), —NR^(d)C(O)NR^(d)R^(e),            —NR^(d)R^(e), —OR^(d), and —S(O)₂NR^(d)R^(e); wherein each            R^(d) and R^(e) is independently selected from hydrogen,            C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached to the same            nitrogen atom can be combined with the nitrogen atom to form            a five or six-membered ring having from 0 to 2 additional            heteroatoms as ring members selected from N, O or S; each            R^(f) is independently selected from the group consisting of            C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,            heterocycloalkyl, aryl and heteroaryl, and wherein the            aliphatic and cyclic portions of R^(d), R^(e) and R^(f) are            optionally further substituted with from one to three            halogen, hydroxy, methyl, amino, alkylamino and dialkylamino            groups;    -   each R³ is independently selected from the group consisting of        -   halogen, —CN, —R^(i), —CO₂R^(g), —CONR^(g)R^(h), —C(O)R^(g),            —OC(O)NR^(g)R^(h), —NR^(h)C(O)R^(g), —NR^(h)C(O)₂R^(i),            —NR^(g)C(O)NR^(g)R^(h), —NR^(g)R^(h), —OR^(g),            —S(O)₂NR^(g)R^(h), —X⁴—R^(j), —X⁴—NR^(g)R^(h),            —X⁴—CONR^(g)R^(h), —X⁴—NR^(h)C(O)R^(g), —NHR^(j) and            —NHCH₂R^(j), wherein X⁴ is a C₁₋₄ alkylene; each R^(g) and            R^(h) is independently selected from hydrogen, C₁₋₈ alkyl,            C₃₋₆ cycloalkyl and C₁₋₈ haloalkyl, or when attached to the            same nitrogen atom can be combined with the nitrogen atom to            form a five or six-membered ring having from 0 to 2            additional heteroatoms as ring members selected from N, O or            S and is optionally substituted with one or two oxo; each            R^(i) is independently selected from the group consisting of            C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,            heterocycloalkyl, aryl and heteroaryl; and each is selected            from the group consisting of C₃₋₆ cycloalkyl, pyrrolinyl,            piperidinyl, morpholinyl, tetrahydrofuranyl, and            tetrahydropyranyl, and wherein the aliphatic and cyclic            portions of R^(g), R^(h), R^(i) and R^(j) are optionally            further substituted with from one to three halogen, methyl,            CF₃, hydroxy, amino, alkylamino and dialkylamino groups; and    -   X is hydrogen or CH₃.

In some embodiments, the compound has the formula (Ie):

wherein p is 0, 1 or 2.

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

A method of reducing proteinuria in a human suffering from orsusceptible to C3 glomerulopathy is provided comprising administering tothe human an effective amount of a compound having the formula (I), or apharmaceutically acceptable salt thereof,

wherein

-   -   C¹ is phenyl optionally substituted with from 1 to 3 R¹        substituents;    -   C² is phenyl optionally substituted with from 1 to 3 R²        substituents;    -   C³ is selected from the group consisting of C₃₋₈ cycloalkyl and        phenyl, and each C³ is optionally substituted with from 1-3 R³        substituents;    -   each R¹ is independently selected from the group consisting of        -   halogen, —CN, —R^(c), —CO₂R^(a), —CONR^(a)R^(b), —C(O)R^(a),            —OC(O)NR^(a)R^(b), —NR^(b)C(O)R^(a), —NR^(b)C(O)₂R^(c),            —NR^(a)C(O)NR^(a)R^(b), —NR^(a)R^(b), —OR^(a), and            —S(O)₂NR^(a)R^(b); wherein each R^(a) and R^(b) is            independently selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈            haloalkyl, or when attached to the same nitrogen atom can be            combined with the nitrogen atom to form a five or            six-membered ring having from 0 to 2 additional heteroatoms            as ring members selected from N, O or S; each R^(c) is            independently selected from the group consisting of C₁₋₈            alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl, heterocycloalkyl,            aryl and heteroaryl, and wherein the aliphatic and cyclic            portions of R^(a), R^(b) and R^(c) are optionally further            substituted with from one to three halogen, hydroxy, methyl,            amino, alkylamino and dialkylamino groups; and optionally            when two R¹ substituents are on adjacent atoms, are combined            to form a fused five or six-membered carbocyclic ring;    -   each R² is independently selected from the group consisting of        -   halogen, —CN, —R^(f), —CO₂R^(d), —CONR^(d)R^(e), —C(O)R^(d),            —OC(O)NR^(d)R^(e), —NR^(e)C(O)R^(d), —NR^(e)C(O)₂R^(f),            —NR^(d)C(O)NR^(d)R^(e), —NR^(d)C(O)NR^(d)R^(e),            —NR^(d)R^(e), —OR^(d), and —S(O)₂NR^(d)R^(e); wherein each            R^(d) and R^(e) is independently selected from hydrogen,            C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached to the same            nitrogen atom can be combined with the nitrogen atom to form            a five or six-membered ring having from 0 to 2 additional            heteroatoms as ring members selected from N, O or S; each            R^(f) is independently selected from the group consisting of            C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,            heterocycloalkyl, aryl and heteroaryl, and wherein the            aliphatic and cyclic portions of R^(d), R^(e) and R^(f) are            optionally further substituted with from one to three            halogen, hydroxy, methyl, amino, alkylamino and dialkylamino            groups;    -   each R³ is independently selected from the group consisting of        -   halogen, —CN, —R^(i), —CO₂R^(g), —CONR^(g)R^(h), —C(O)R^(g),            —OC(O)NR^(g)R^(h), —NR^(h)C(O)R^(g), —NR^(h)C(O)₂R^(i),            —NR^(g)C(O)NR^(g)R^(h), —NR^(g)R^(h), —OR^(g),            —S(O)₂NR^(g)R^(h), —X⁴—R^(j), —X⁴—NR^(g)R^(h),            —X⁴—CONR^(g)R^(h), —X⁴—NR^(h)C(O)R^(g), —NHR^(j) and            —NHCH₂R^(j), wherein X⁴ is a C₁₋₄ alkylene; each R^(g) and            R^(h) is independently selected from hydrogen, C₁₋₈ alkyl,            C₃₋₆ cycloalkyl and C₁₋₈haloalkyl, or when attached to the            same nitrogen atom can be combined with the nitrogen atom to            form a five or six-membered ring having from 0 to 2            additional heteroatoms as ring members selected from N, O or            S and is optionally substituted with one or two oxo; each            R^(i) is independently selected from the group consisting of            C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,            heterocycloalkyl, aryl and heteroaryl; and each is selected            from the group consisting of C₃₋₆ cycloalkyl, pyrrolinyl,            piperidinyl, morpholinyl, tetrahydrofuranyl, and            tetrahydropyranyl, and wherein the aliphatic and cyclic            portions of R^(g), R^(h), R^(i) and R^(j) are optionally            further substituted with from one to three halogen, methyl,            CF₃, hydroxy, amino, alkylamino and dialkylamino groups; and    -   X is hydrogen or CH₃.

In some embodiments, the compound has the formula (Ie):

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the human suffers from complement 3glomerulonephritis. In some embodiments, the human suffers fromprogressive complement 3 glomerulonephritis. In some embodiments, thehuman suffers from recurrent complement 3 glomerulonephritis after arenal transplant. In some embodiments, the human suffers from densedeposit disease. In some embodiments, the human had refractory diseaseto immunosuppressive drugs.

A method of treating a human suffering from or susceptible to complement3 glomerulopathy is provided comprising administering to the human aneffective amount of a compound having the formula (Ie), or apharmaceutically acceptable salt thereof,

wherein

-   -   each R¹ is independently selected from the group consisting of        -   halogen, —CN, —R^(c), —CO₂R^(a), —CONR^(a)R^(b), —C(O)R^(a),            —OC(O)NR^(a)R^(b), —NR^(b)C(O)R^(a), —NR^(b)C(O)₂R^(c),            —NR^(a)C(O)NR^(a)R^(b), —OR^(a), and —S(O)₂NR^(a)R^(b);            wherein each R^(a) and R^(b) is independently selected from            hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached            to the same nitrogen atom can be combined with the nitrogen            atom to form a five or six-membered ring having from 0 to 2            additional heteroatoms as ring members selected from N, O or            S; each R^(c) is independently selected from the group            consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,            heterocycloalkyl, aryl and heteroaryl, and wherein the            aliphatic and cyclic portions of R^(a), R^(b) and R^(c) are            optionally further substituted with from one to three            halogen, hydroxy, methyl, amino, alkylamino and dialkylamino            groups; and optionally when two R¹ substituents are on            adjacent atoms, are combined to form a fused five or            six-membered carbocyclic ring;    -   each R² is independently selected from the group consisting of        -   halogen, —CN, —R^(f), —CO₂R^(d), —CONR^(d)R^(e), —C(O)R^(d),            —OC(O)NR^(d)R^(e), —NR^(e)C(O)R^(d), —NR^(e)C(O)₂R^(f),            —NR^(d)C(O)NR^(d)R^(e), —NR^(d)C(O)NR^(d)R^(e),            —NR^(d)R^(e), —OR^(d), and —S(O)₂NR^(d)R^(e); wherein each            R^(d) and R^(e) is independently selected from hydrogen,            C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached to the same            nitrogen atom can be combined with the nitrogen atom to form            a five or six-membered ring having from 0 to 2 additional            heteroatoms as ring members selected from N, O or S; each            R^(f) is independently selected from the group consisting of            C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,            heterocycloalkyl, aryl and heteroaryl, and wherein the            aliphatic and cyclic portions of R^(d), R^(e) and R^(f) are            optionally further substituted with from one to three            halogen, hydroxy, methyl, amino, alkylamino and dialkylamino            groups;    -   each R³ is independently selected from the group consisting of        -   halogen, —CN, —R^(i), —CO₂R^(g), —CONR^(g)R^(h), —C(O)R^(g),            —OC(O)NR^(g)R^(h), —NR^(h)C(O)R^(g), —NR^(h)C(O)₂R^(i),            —NR^(g)C(O)NR^(g)R^(h), —NR^(g)R^(h), —OR^(g),            —S(O)₂NR^(g)R^(h), —X⁴—R^(j), —X⁴—NR^(g)R^(h),            —X⁴—CONR^(g)R^(h), —X⁴—NR^(h)C(O)R^(g), —NHR^(j) and            —NHCH₂R^(j), wherein X⁴ is a C₁₋₄ alkylene; each R^(g) and            R^(h) is independently selected from hydrogen, C₁₋₈ alkyl,            C₃₋₆ cycloalkyl and C₁₋₈ haloalkyl, or when attached to the            same nitrogen atom can be combined with the nitrogen atom to            form a five or six-membered ring having from 0 to 2            additional heteroatoms as ring members selected from N, O or            S and is optionally substituted with one or two oxo; each            R^(i) is independently selected from the group consisting of            C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,            heterocycloalkyl, aryl and heteroaryl; and each R^(j) is            selected from the group consisting of C₃₋₆ cycloalkyl,            pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and            tetrahydropyranyl, and wherein the aliphatic and cyclic            portions of R^(g), R^(h), R^(i) and R^(j) are optionally            further substituted with from one to three halogen, methyl,            CF₃, hydroxy, amino, alkylamino and dialkylamino groups; and    -   p is 0, 1 or 2.

In some embodiments,

-   -   each R¹ is independently selected from the group consisting of        halogen, —CN, —R^(c), —NR^(a)R^(b), and —OR^(a); wherein each        R^(a) and R^(b) is independently selected from hydrogen, C₁₋₈        alkyl, and C₁₋₈ haloalkyl, or when attached to the same nitrogen        atom can be combined with the nitrogen atom to form a        pyrrolidine ring; each R^(c) is independently selected from the        group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl        and wherein the aliphatic and cyclic portions of R^(a), R^(b)        and R^(c) are optionally further substituted with from one to        three hydroxy, methyl, amino, alkylamino and dialkylamino        groups; and optionally when two R¹ substituents are on adjacent        atoms, are combined to form a fused five or six-membered        carbocyclic ring;    -   each R² is independently selected from the group consisting of        halogen, —R^(f), and —OR^(d); wherein each R^(d) is        independently selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈        haloalkyl, each R^(f) is independently selected from the group        consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,        heterocycloalkyl and heteroaryl, and wherein the aliphatic and        cyclic portions of R^(d) and R^(f) are optionally further        substituted with from one to three halogen, hydroxy, methyl,        amino, alkylamino and dialkylamino groups;    -   each R³ is independently selected from the group consisting of        halogen, —R^(i), —CO₂R^(g), —CONR^(g)R^(h), —NR^(h)C(O)R^(g),        -   —NR^(h)C(O)₂R^(i), —NR^(g)R^(h), —OR^(g), —X⁴—R^(j),            —X⁴—NR^(g)R^(h), —X⁴—CONR^(g)R^(h), —X⁴—NR^(h)C(O)R^(g),            —NHR^(j) and —NHCH₂R^(j), wherein X⁴ is a C₁₋₄ alkylene;            each R^(g) and R^(h) is independently selected from            hydrogen, C₁₋₈ alkyl, C₃₋₆ cycloalkyl and C₁₋₈ haloalkyl, or            when attached to the same nitrogen atom can be combined with            the nitrogen atom to form a five or six-membered ring having            from 0 to 2 additional heteroatoms as ring members selected            from N, O or S and is optionally substituted with one or two            oxo; each R^(i) is independently selected from the group            consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,            heterocycloalkyl, aryl and heteroaryl; and each R^(j) is            selected from the group consisting of C₃₋₆ cycloalkyl,            pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and            tetrahydropyranyl, and wherein the aliphatic and cyclic            portions of R^(g), R^(h), R^(i) and R^(j) are optionally            further substituted with from one to three halogen, methyl,            CF₃, hydroxy, amino, alkylamino and dialkylamino groups; and    -   p is 1.

In Some Embodiments,

-   -   each R¹ is independently selected from the group consisting of        C₁₋₈ alkyl and C₁₋₈ haloalkyl;    -   each R² is independently selected from the group consisting of        halogen and C₁₋₈ alkyl;    -   each R³ is —NR^(g)R^(h) wherein each R^(g) and R^(h) is        independently selected from hydrogen and C₃₋₆ cycloalkyl; and    -   p is 1.

In Some Embodiments,

-   -   each R¹ is independently selected from the group consisting of        C₁₋₃ alkyl and C₁₋₃ haloalkyl;    -   each R² is independently selected from the group consisting of        halogen and C₁₋₃ alkyl;    -   each R³ is —NR^(g)R^(h) wherein each R^(g) and R^(h) is        independently selected from hydrogen and C₄₋₆ cycloalkyl; and    -   p is 1.

In some embodiments, the compound is selected from the group consistingof

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the method comprises one or more of: slowing therate of decline in Estimated Glomerular Filtration Rate (eGFR) in thehuman, reducing glomerular inflammation in the human, clearingglomerular endocapillary proliferation in the human, reducing glomerularinflammatory macrophages in the human, reducing proteinuria in thehuman, slowing down the progression of renal disease in the human,stopping the progression of renal disease in the human, delaying endstage renal disease in the human, improving renal histology in thehuman, decreasing proteinuria in the human, slowing the increase inproteinuria in the human. In some embodiments, the improvements may besupported by kidney biopsy.

A method of slowing the rate of decline in Estimated GlomerularFiltration Rate (eGFR) in a human suffering from or susceptible to C3glomerulopathy is provided comprising administering to the human aneffective amount of a compound having the following formula:

or a pharmaceutically acceptable salt thereof.

A method of slowing the rate of decline in Estimated GlomerularFiltration Rate (eGFR) in a human suffering from or susceptible to C3glomerulopathy is provided comprising administering to the human aneffective amount of a compound having the following formula:

or a pharmaceutically acceptable salt thereof.

A method of reducing glomerular inflammation in a human suffering fromor susceptible to C3 glomerulopathy is provided comprising administeringto the human an effective amount of a compound having the followingformula:

or a pharmaceutically acceptable salt thereof.

A method of reducing glomerular inflammation in a human suffering fromor susceptible to C3 glomerulopathy is provided comprising administeringto the human an effective amount of a compound having the followingformula:

or a pharmaceutically acceptable salt thereof.

A method of reducing C3 deposits and/or C5b-9 deposits in a humansuffering from or susceptible to C3 glomerulopathy is providedcomprising administering to the human an effective amount of a compoundhaving the following formula:

or a pharmaceutically acceptable salt thereof.

A method of reducing C3 deposits and/or C5b-9 deposits in a humansuffering from or susceptible to C3 glomerulopathy is providedcomprising administering to the human an effective amount of a compoundhaving the following formula:

or a pharmaceutically acceptable salt thereof.

A method of clearing glomerular endocapillary proliferation in a humansuffering from or susceptible to C3 glomerulopathy is providedcomprising administering to the human an effective amount of a compoundhaving the following formula:

or a pharmaceutically acceptable salt thereof.

A method of clearing glomerular endocapillary proliferation in a humansuffering from or susceptible to C3 glomerulopathy is providedcomprising administering to the human an effective amount of a compoundhaving the following formula:

or a pharmaceutically acceptable salt thereof.

A method of reducing glomerular inflammatory macrophages in a humansuffering from or susceptible to C3 glomerulopathy is providedcomprising administering to the human an effective amount of a compoundhaving the following formula:

or a pharmaceutically acceptable salt thereof.

A method of reducing glomerular inflammatory macrophages in a humansuffering from or susceptible to C3 glomerulopathy is providedcomprising administering to the human an effective amount of a compoundhaving the following formula:

or a pharmaceutically acceptable salt thereof.

A method of reducing proteinuria in a human suffering from orsusceptible to C3 glomerulopathy is provided comprising administering tothe human an effective amount of a compound having the followingformula:

or a pharmaceutically acceptable salt thereof.

A method of reducing proteinuria in a human suffering from orsusceptible to C3 glomerulopathy is provided comprising administering tothe human an effective amount of a compound having the followingformula:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the human suffers from complement 3glomerulonephritis. In some embodiments, the human suffers fromprogressive complement 3 glomerulonephritis. In some embodiments, thehuman suffers from recurrent complement 3 glomerulonephritis after arenal transplant. In some embodiments, the human suffers from densedeposit disease.

In some embodiments, the complement 3 glomerulopathy is refractory totreatment. In some embodiments, the complement 3 glomerulonephritis isrefractory to other treatment. In some embodiments, the human hasrefractory disease to immunosuppressive drugs. In some embodiments, thehuman has refractory disease to one or more of rituximab,cyclophosphamide, mycophenolate mofetil, tacrolimus, and steroids. Insome embodiments, the human has refractory disease to one or more ofrituximab, cyclophosphamide, mycophenolate mofetil, tacrolimus, andglucocorticosteroids. In some embodiments, the human shows improvedhealth-related quality of life changes. In some embodiments, thehealth-related quality-of-life is based on Short Form-36 version 2(SF-36 v2) or EuroQOL-5D-5L (EQ-5D-5L) assessment. In some embodiments,the health-related quality-of-life is based on Short Form-36 version 2(SF-36 v2) assessment. In some embodiments, the health-relatedquality-of-life is based on EuroQOL-5D-5L (EQ-5D-5L) assessment.

In some embodiments, the compound is administered twice daily. In someembodiments, the compound is administered once a day. In someembodiments, the compound is administered every other day. In someembodiments, the compound is administered every 3 days. In someembodiments, the compound is administered 3 times per day. In someembodiments, the compound is administered 4 times per day.

In some embodiments, the human receives 30 mg of the compound daily. Insome embodiments, the human receives 20 mg of the compound daily. Insome embodiments, the human receives 10 mg of the compound daily. Insome embodiments, the human receives 40 mg of the compound daily. Insome embodiments, the human receives 60 mg of the compound daily. Insome embodiments, the human receives 50 mg, 70 mg, 80 mg, 90 mg, 100 mg,150 mg or 200 mg of the compound daily.

In some embodiments, the human receives 30 mg of the compound twicedaily. In some embodiments, the human receives 20 mg of the compoundtwice daily. In some embodiments, the human receives 10 mg of thecompound twice daily.

In some embodiments, the compound is administered orally.

In some embodiments, the human has a Complement factor H related protein5 (CFHR5) mutation.

In some embodiments, the human receives treatment for 12 weeks. In someembodiments, the human receives treatment for 26 weeks. In someembodiments, the human receives treatment for 52 weeks. In someembodiments, the human receives chronic treatment. In some embodiments,the human receives continuous treatment.

In some embodiments, the method further comprises administering to thehuman a therapeutically effective amount of one or more additionaltherapeutic agents. In some embodiments, the one or more additionaltherapeutic agents is administered sequentially or concurrently in thesame composition or not.

In some embodiments, the one or more additional therapeutic agents isselected from immunosuppressive drugs, angiotensin-converting enzyme(ACE) inhibitors, angiotensin II type-1 receptor blockers (ARBs) andcorticosteroids.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of cyclophosphamide, mycophenolatemofetil, rituximab, eculizumab, tacrolimus, belimumab, OMS721, ACH-4471,AMY-101, Acthar Gel, SAND-5, corticotropin, CDX-1135, ramipril,perindopril, lisinopril, perindopril arginine, captopril, spirapril,quinapril, enalapril, imidapril, fosinopril, zofenopril, benazepril,trandolapril, verapamil, benazepril, amlodipine, trandolapril, P-003,cilazapril, delapril, moexipril, quinapril, fosinopril, temocapril,losartan, candesartan, irbesartan, telmisartan, olmesartan, valsartan,azilsartan, telmisartan, fimasartan, EMA-401, azilsartan medoxomilpotassium, sparsentan, candesartan cilexetil, olmesartan medoxomil,TRV-027, losartan potassium, YH-22189, azilsartan trimethylethanolamine,allisartan isoproxil, and eprosartan. In some embodiments, the one ormore additional therapeutic agents is selected from the group consistingof cyclophosphamide, mycophenolate mofetil, rituximab, eculizumab, andtacrolimus.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of corticosteroids, steroids,immunosuppressants, Immunoglobulin G agonists, Dipeptidyl peptidase IVinhibitors, Lymphocyte function antigen-3 receptor antagonists,Interleukin-2 ligands, Interleukin-1 beta ligand inhibitors, IL-2receptor alpha subunit inhibitors, HGF gene stimulators, IL-6antagonists, IL-5 antagonists, Alpha 1 antitrypsin stimulators,Cannabinoid receptor antagonists, Histone deacetylase inhibitors, AKTprotein kinase inhibitors, CD20 inhibitors, Ab1 tyrosine kinaseinhibitors, JAK tyrosine kinase inhibitors, TNF alpha ligand inhibitors,Hemoglobin modulators, TNF antagonists, proteasome inhibitors, CD3modulators, Hsp 70 family inhibitors, Immunoglobulin agonists, CD30antagonists, tubulin antagonists, Sphingosine-1-phosphate receptor-1agonists, connective tissue growth factor ligand inhibitors, caspaseinhibitors, adrenocorticotrophic hormone ligands, Btk tyrosine kinaseinhibitors, Complement C1s subcomponent inhibitors, Erythropoietinreceptor agonists, B-lymphocyte stimulator ligand inhibitors,Cyclin-dependent kinase-2 inhibitors, P-selectin glycoprotein ligand-1stimulators, mTOR inhibitors, Elongation factor 2 inhibitors, Celladhesion molecule inhibitors, Factor XIII agonists, Calcineurininhibitors, Immunoglobulin G1 agonists, Inosine monophosphatedehydrogenase inhibitors, Complement C1s subcomponent inhibitors,Thymidine kinase modulators, Cytotoxic T-lymphocyte protein-4modulators, Angiotensin II receptor antagonists, Angiotensin II receptormodulators, TNF superfamily receptor 12A antagonists, CD52 antagonists,Adenosine deaminase inhibitors, T-cell differentiation antigen CD6inhibitors, FGF-7 ligands, dihydroorotate dehydrogenase inhibitors, CCR5chemokine antagonists, CCR2 chemokine antagonists, Syk tyrosine kinaseinhibitors, Interferon type I receptor antagonists, Interferon alphaligand inhibitors, Macrophage migration inhibitory factor inhibitors,Integrin alpha-V/beta-6 antagonists, Cysteine protease stimulators, p38MAP kinase inhibitors, TP53 gene inhibitors, Shiga like toxin Iinhibitors, Fucosyltransferase 6 stimulators, Interleukin 22 ligands,CXCR1 chemokine antagonists, CXCR4 chemokine antagonists, IRS1 geneinhibitors, Protein kinase C stimulators, Protein kinase C alphainhibitors, CD74 antagonists, Immunoglobulin gamma Fc receptor IIBantagonists, T-cell antigen CD7 inhibitors, CD95 antagonists, Nacetylmannosamine kinase stimulators, Cardiotrophin-1 ligands, Leukocyteelastase inhibitors, CD40 ligand receptor antagonists, CD40 ligandmodulators, IL-17 antagonists, TLR-2 antagonists, complement factor Dinhibitors, complement factor B inhibitors, complement C5 inhibitors,MASP-2 inhibitors, MASP-3 inhibitors, C3 inhibitors, pegylated APL-1,C1s inhibitors, C6 inhibitors, and T cell receptor antagonists.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of obinutuzumab, rituximab,ocrelizumab, cyclophosphamide, prednisone, hydrocortisone,hydrocortisone acetate, cortisone acetate, tixocortol pivalate,prednisolone, methylprednisolone, triamcinolone acetonide, triamcinolonealcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide,fluocinolone acetonide, halcinonide, betamethasone, betamethasone sodiumphosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone,hydrocortisone-17-valerate, halometasone, alclometasone dipropionate,beclomethasone, betamethasone valerate, betamethasone dipropionate,prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate,fluocortolone caproate, fluocortolone pivalate, fluprednidene acetate,hydrocortisone-17-butyrate, hydrocortisone-17-aceponate,hydrocortisone-17-buteprate, ciclesonide and prednicarbate, GB-0998,immuglo, begelomab, alefacept, aldesleukin, gevokizumab, daclizumab,basiliximab, inolimomab, beperminogene perplasmid, sirukumab,tocilizumab, clazakizumab, mepolizumab, fingolimod, panobinostat,triciribine, nilotinib, imatinib, tofacitinib, momelotinib, peficitinib,itacitinib, infliximab, PEG-bHb-CO, etanercept, ixazomib, bortezomib,muromonab, otelixizumab, gusperimus, brentuximab vedotin, Ponesimod,KRP-203, FG-3019, emricasan, corticotropin, ibrutinib, cinryze,conestat, methoxy polyethylene glycol-epoetin beta, belimumab,blisibimod, atacicept, seliciclib, neihulizumab, everolimus, sirolimus,denileukin diftitox, LMB-2, natalizumab, catridecacog, ciclosporin,tacrolimus, voclosporin, voclosporin, canakinumab, mycophenolate,mizoribine, CE-1145, TK-DLI, abatacept, belatacept, olmesartanmedoxomil, sparsentan, TXA-127, BIM-023, alemtuzumab, pentostatin,itolizumab, palifermin, leflunomide, PRO-140, cenicriviroc,fostamatinib, anifrolumab, sifalimumab, BAX-069, BG-00011, losmapimod,QPI-1002, ShigamAbs, TZ-101, F-652, reparixin, ladarixin, PTX-9908,aganirsen, APH-703, sotrastaurin, sotrastaurin, milatuzumab, SM-101,T-Guard, APG-101, DEX-M74, cardiotrophin-1, tiprelestat, ASKP-1240,BMS-986004, HPH-116, KD-025, OPN-305, TOL-101, defibrotide,pomalidomide, Thymoglobulin, laquinimod, remestemcel-L, Equineantithymocyte immunoglobulin, Stempeucel, LIV-Gamma, Octagam 10%,t2c-001, 99mTc-sestamibi, Clairyg, Prosorba, pomalidomide, laquinimod,teplizumab, FCRx, solnatide, foralumab, ATIR-101, BPX-501, ACP-01,ALLO-ASC-DFU, irbesartan+propagermanium, ApoCell, cannabidiol, RGI-2001,saratin, anti-CD3 bivalent antibody-diphtheria toxin conjugate, OMS-721,eculizumab, coversin, ACH-4471, ALN-CCS, AMY-101, IFX-1, IFX-2, IFX-3,LFG316, berinert, CB 2782, ANX005, APL-2, APL-1, PEG-Cp40, ALXN1007,bikaciomab, NOX-D20, NOX-D19, OMS906, mubodina, ALXN1210, ruconest,TNT009, SOBI005, SHP623, cinryze, lampalizumab, regenemab, RA101495,RA101295, zimura, NOX-100, LT-1951, and CD4+CD25+ regulatory T-cells.

Certain compounds of the present disclosure can exist in unsolvatedforms as well as solvated forms, including hydrated forms. In general,the solvated forms are equivalent to unsolvated forms and are intendedto be encompassed within the scope of the present disclosure. Certaincompounds of the present disclosure may exist in multiple crystalline oramorphous forms. In general, all physical forms are equivalent for theuses contemplated by the present disclosure and are intended to bewithin the scope of the present disclosure.

Certain compounds of the present disclosure possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers, regioisomers and individual isomers (e.g., separateenantiomers) are all intended to be encompassed within the scope of thepresent disclosure. The compounds of the present disclosure may alsocontain unnatural proportions of atomic isotopes at one or more of theatoms that constitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present disclosure, whether radioactive or not, areintended to be encompassed within the scope of the present disclosure.

The compounds disclosed herein are also meant to encompass allpharmaceutically acceptable compounds of Formulas (I), (Ia), (Ib), (Ic),(Id), (Ie) and compound 1 being isotopically-labeled by having one ormore atoms replaced by an atom having a different atomic mass or massnumber. Examples of isotopes that can be incorporated into the disclosedcompounds include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I,respectively. These radiolabeled compounds could be useful to helpdetermine or measure the effectiveness of the compounds, bycharacterizing, for example, the site or mode of action, or bindingaffinity to pharmacologically important site of action. Certainisotopically-labeled compounds of Formulas (I), (Ia), (Ib), (Ic), (Id),(Ie) and compound 1 for example, those incorporating a radioactiveisotope, are useful in drug and/or substrate tissue distributionstudies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e.¹⁴C, are particularly useful for this purpose in view of their ease ofincorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability. For example, in vivo half-life may increase or dosagerequirements may be reduced. Thus, heavier isotopes may be preferred insome circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie) and compound 1 cangenerally be prepared by conventional techniques known to those skilledin the art or by processes analogous to those described in the Examplesas set out below using an appropriate isotopically-labeled reagent inplace of the non-labeled reagent previously employed.

The methods, compositions, kits and articles of manufacture providedherein use or include compounds (e.g., (I), (Ia), (Ib), (Ic), (Id), (Ie)and compound 1) or pharmaceutically acceptable salts, prodrugs, orsolvates thereof, in which from 1 to n hydrogen atoms attached to acarbon atom may be replaced by a deuterium atom or D, in which n is thenumber of hydrogen atoms in the molecule. As known in the art, thedeuterium atom is a non-radioactive isotope of the hydrogen atom. Suchcompounds may increase resistance to metabolism, and thus may be usefulfor increasing the half-life of compounds or pharmaceutically acceptablesalts, prodrugs, or solvates thereof, when administered to a mammal.See, e.g., Foster, “Deuterium Isotope Effects in Studies of DrugMetabolism”, Trends Pharmacol. Sci., 5 (12):524-527 (1984). Suchcompounds are synthesized by means well known in the art, for example byemploying starting materials in which one or more hydrogen atoms havebeen replaced by deuterium.

Treatment methods provided herein include, in general, administration toa patient an effective amount of the compounds provided herein. Suitablepatients include those patients suffering from or susceptible to (i.e.,prophylactic treatment) C3 glomerulonephritis.

In general, treatment methods provided herein comprise administering toa patient an effective amount of a compound provided herein. In apreferred embodiment, the compound(s) of the disclosure are preferablyadministered to a patient (e.g., a human) orally or topically. Inanother embodiment, the compound(s) of the disclosure are administeredto a patient (e.g., a human) systemically (intravenously orsubcutaneously). The effective amount may be an amount sufficient tomodulate C5a receptor activity and/or an amount sufficient to reduce oralleviate the symptoms presented by the patient. Preferably, the amountadministered is sufficient to yield a plasma concentration of thecompound (or its active metabolite, if the compound is a pro-drug) highenough to detectably inhibit white blood cell (e.g., neutrophil)chemotaxis in vitro. Treatment regimens may vary depending on thecompound used and the particular condition to be treated; for treatmentof most disorders, a frequency of administration of 4 times daily orless is preferred. In general, a dosage regimen of 2 times daily is morepreferred, with once a day dosing particularly preferred. It will beunderstood, however, that the specific dose level and treatment regimenfor any particular patient will depend upon a variety of factorsincluding the activity of the specific compound employed, the age, bodyweight, general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination (i.e., other drugsbeing administered to the patient) and the severity of the particulardisease undergoing therapy, as well as the judgment of the prescribingmedical practitioner. In general, the use of the minimum dose sufficientto provide effective therapy is preferred. Patients may generally bemonitored for therapeutic effectiveness using medical or veterinarycriteria suitable for the condition being treated or prevented.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment orpreventions of conditions involving pathogenic C5a activity (about 0.5mg to about 7 g per human patient per day). The amount of activeingredient that may be combined with the carrier materials to produce asingle dosage form will vary depending upon the host treated and theparticular mode of administration. Dosage unit forms will generallycontain between from about 1 mg to about 500 mg of an active ingredient.For compounds administered orally, transdermally, intravenously, orsubcutaneously, it is preferred that sufficient amount of the compoundbe administered to achieve a serum concentration of 5 ng(nanograms)/mL-10 μg (micrograms)/mL serum, more preferably sufficientcompound to achieve a serum concentration of 20 ng-1 μg/ml serum shouldbe administered, most preferably sufficient compound to achieve a serumconcentration of 50 ng/ml-200 ng/ml serum should be administered. Fordirect injection into the synovium (for the treatment of arthritis)sufficient compounds should be administered to achieve a localconcentration of approximately 1 micromolar.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. However, for treatment of most disorders, adosage regimen of 4 times daily, three times daily, or less ispreferred, with a dosage regimen of once daily or 2 times daily beingparticularly preferred. It will be understood, however, that thespecific dose level for any particular patient will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, general health, sex, diet, time ofadministration, route of administration, and rate of excretion, drugcombination (i.e., other drugs being administered to the patient), theseverity of the particular disease undergoing therapy, and otherfactors, including the judgment of the prescribing medical practitioner.

Pharmaceutical Compositions

The compounds provided herein can be administered as compositions whichwill typically contain a pharmaceutical carrier or diluent.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts.

In some embodiments, the pharmaceutical composition further comprisesone or more additional therapeutic agents.

The pharmaceutical compositions for the administration of the compoundsof this disclosure may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacyand drug delivery. All methods include the step of bringing the activeingredient into association with the carrier which constitutes one ormore accessory ingredients. In general, the pharmaceutical compositionsare prepared by uniformly and intimately bringing the active ingredientinto association with a liquid carrier or a finely divided solid carrieror both, and then, if necessary, shaping the product into the desiredformulation. In the pharmaceutical composition the active objectcompound is included in an amount sufficient to produce the desiredeffect upon the process or condition of diseases.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions and self-emulsifications as described in U.S. PatentApplication 2002-0012680, hard or soft capsules, syrups, elixirs,solutions, buccal patch, oral gel, chewing gum, chewable tablets,effervescent powder and effervescent tablets. Compositions intended fororal use may be prepared according to any method known to the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents, antioxidants andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as cellulose, silicon dioxide, aluminumoxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example PVP, cellulose, PEG, starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated,enterically or otherwise, by known techniques to delay disintegrationand absorption in the gastrointestinal tract and thereby provide asustained action over a longer period. For example, a time delaymaterial such as glyceryl monostearate or glyceryl distearate may beemployed. They may also be coated by the techniques described in theU.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, polyethyleneglycol (PEG) of various average sizes (e.g., PEG400, PEG4000) andcertain surfactants such as cremophor or solutol, or as soft gelatincapsules wherein the active ingredient is mixed with water or an oilmedium, for example peanut oil, liquid paraffin, or olive oil.Additionally, emulsions can be prepared with a non-water miscibleingredient such as oils and stabilized with surfactants such as mono- ordi-glycerides, PEG esters and the like.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxy-ethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the disclosure may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oil,for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. Oral solutions can be prepared in combination with, for example,cyclodextrin, PEG and surfactants.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present disclosure may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include cocoa butter andpolyethylene glycols. Additionally, the compounds can be administeredvia ocular delivery by means of solutions or ointments. Still further,transdermal delivery of the subject compounds can be accomplished bymeans of iontophoretic patches and the like. For topical use, creams,ointments, jellies, solutions or suspensions, etc., containing thecompounds of the present disclosure are employed. As used herein,topical application is also meant to include the use of mouth washes andgargles.

The compounds of this disclosure may also be coupled a carrier that is asuitable polymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxy-propyl-methacrylamide-phenol,polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thedisclosure may be coupled to a carrier that is a class of biodegradablepolymers useful in achieving controlled release of a drug, for examplepolylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross linked or amphipathic block copolymers of hydrogels. Polymers andsemipermeable polymer matrices may be formed into shaped articles, suchas valves, stents, tubing, prostheses and the like. In one embodiment ofthe disclosure, the compound of the disclosure is coupled to a polymeror semipermeable polymer matrix that is formed as a stent or stent-graftdevice.

Kits and Packages

The terms “kit” and “pharmaceutical kit” refer to a commercial kit orpackage comprising, in one or more suitable containers, one or morepharmaceutical compositions and instructions for their use. In oneembodiment, kits comprising a compound of Formula (I), (Ia), (Ib), (Ic),(Id) or (Ie), or compound 1, or a pharmaceutically acceptable saltthereof, and instructions for its administration are provided. In oneembodiment, kits comprising a compound of Formula (I), (Ia), (Ib), (Ic),(Id) or (Ie), or compound 1, or a pharmaceutically acceptable saltthereof, in combination with one or more (e.g., one, two, three, one ortwo, or one to three) additional therapeutic agents and instructions fortheir administration are provided.

In one embodiment, the compounds of this disclosure are formulated intoadministration units which are packaged in a single packaging. Thesingle packaging encompasses but is not limited to a bottle, achild-resistant bottle, an ampoule, and a tube. In one embodiment, thecompounds of this disclosure and optionally additional therapeuticagents, are formulated into administration units and every singleadministration unit is individually packaged in a single packaging. Suchindividually packaged units may contain the pharmaceutical compositionin any form including but not limited to liquid form, solid form, powderform, granulate form, an effervescent powder or tablet, hard or softcapsules, emulsions, suspensions, syrup, suppositories, tablet, troches,lozenges, solution, buccal patch, thin film, oral gel, chewable tablet,chewing gum, and single-use syringes. Such individually packaged unitsmay be combined in a package made of one or more of paper, cardboard,paperboard, metal foil and plastic foil, for example a blister pack. Oneor more administration units may be administered once or several times aday. One or more administration units may be administered three times aday. One or more administration units may be administered twice a day.One or more administration units may be administered on a first day andone or more administration units may be administered on the followingdays.

Compound 1 has the formula:

EXAMPLES Example 1 Study of Compound 1 in a Patient with ProgressiveComplement 3 Glomerulonephritis

Under the Special Needs program in the United Kingdom (which is similarto a compassionate use protocol in the US), a C3 glomerulonephritispatient received treatment with the orally administered complementinhibitor compound 1, following the protocol detailed below. The patienthad refractory disease despite a kidney transplant and prior treatmentwith the broadly immunosuppressive drugs rituximab, cyclophosphamide,mycophenolate mofetil, tacrolimus, and steroids. Renal allograftbiopsies were taken pre-dose, 2 and 7 months during therapy.

Results

The patient's condition improved in response to compound 1 treatment.The improvement seen with compound 1 treatment in this patient was basedon the on-treatment kidney biopsy histologic findings that showedclearance of glomerular endocapillary proliferation and a markeddecrease in glomerular inflammatory macrophages compared to thepre-treatment biopsy. Proteinuria dropped approximately 80% withcompound 1 treatment.

Estimated glomerular filtration rate (eGFR) was 83 mL/min/1.73 m² 14months prior to treatment with compound 1 and deteriorated to 46mL/min/1.73 m² when treatment with compound 1 was started. Treatmentwith compound 1 attenuated or stopped the eGFR decline.

After 1 month of treatment, the eGFR decline was already attenuated(FIG. 1 shows the eGFR prior and after treatment with compound 1).Repeat biopsies showed resolution of glomerular endocapillaryhypercellularity and reduction in glomerular macrophages. Compound 1stabilized eGFR and reduced glomerular inflammation.

TABLE 1 Endocapillary hypercellularity, Immunoflourescence microscopyand CD68-positive cells/glomerulus at different time points.Endocapillary hypercellularity/ Immunoflourescence CD68-positive totalmicroscopy cells/glomerulus Pre-treatment 3/11 C3, 2+; IgM, trace 11 2months 0/36 C3, 2+; IgM, neg 2-3 7 months 0/14 C3, 2+; IgM, neg 1-2

FIG. 2 represents the histopathological improvement following treatmentwith compound 1.

-   -   (A) Haematoxylin and Eosin (H&E) staining before treatment with        compound 1 demonstrates fibrinoid necrosis and multiple        inflammatory cells.    -   (C) Periodic acid-Schiff (PAS) staining after treatment with        compound 1 shows a reduction in endocapillary hypercellularity        and glomerular inflammation.    -   (B) CD68 staining before treatment with compound 1.    -   (D) CD68 staining after treatment with compound 1 demonstrates a        reduction in glomerular macrophages.        Protocol of the Study        Aim

The aim of this study is to evaluate the efficacy, safety, andtolerability of compound 1 in a patient with progressive complement 3(C3) glomerulonephritis.

Objectives

The primary safety objective of this study is to evaluate the safety andtolerability of compound 1.

The primary efficacy objective is to evaluate the efficacy of compound 1based on change from baseline in eGFR (MDRD, Estimated GlomerularFiltration Rate) and proteinuria.

The secondary objectives of this study include assessment of:

-   -   1. Change from baseline in pharmacodynamic markers in plasma and        urine, e.g., MCP-1, C3a, C5a, properdin, and sC5b-9;    -   2. Change from baseline in glomerular pathology based on renal        biopsy;    -   3. Evaluation of the plasma concentrations of compound 1 in C3        glomerulonephritis.        Methodology

This is a clinical study to test the safety, tolerability, and efficacyof compound 1 in a patient with recurrent C3GN in a renal transplant.

The patient will have biopsy proven recurrent C3GN prior to start ofdosing, and be deemed eligible based on the inclusion and exclusioncriteria. Screening procedures will include recording of demographics,medical history, medication history, physical examination and vitalsigns, serum chemistry, hematology, urinalysis (including UPCRmeasurement), viral screening (if not performed within prior 12 weeks),and estimated glomerular filtration rate (eGFR) assessment based onserum creatinine. The baseline eGFR needs to be at least 25 mL/min/1.73m² for study eligibility.

On Day 1, the patient will start compound 1 treatment. Patients willtake compound 1 30 mg orally twice daily for an initial period of 84days. The patient will visit the study center on Days 1, 8, 15, 29, 57,and 85. The compound 1 dose will be taken in the morning optimallywithin one hour after breakfast and in the evening optimally within onehour after dinner. If the patient's clinical condition stabilizes orimproves, and there are no adverse events preventing further treatment,the patient may be treated for another 84-day treatment cycle. The84-day cycles may be repeated for a total of up to 4 cycles under thisprotocol. For the 84-day cycles after the first cycle, the patient willvisit the study center every 4 weeks. There will be 4-week follow-upperiod after the patient stops the compound 1 treatment.

At the Day 1 and post-Day 1 study visits, blood and urine samples willbe collected for safety, efficacy, and pharmacokinetic measurements.Physical examinations and vital signs assessments will be performedthroughout the study. Concomitant medication and adverse eventassessments will be made at every study visit. If at all possible, arenal biopsy will be performed after an appropriate follow-up period toassess the changes in kidney histology.

No new treatment for C3 GN may be added during the study period (activetreatment period or follow up), unless the subject's conditiondeteriorates to the extent that the investigator deems it in the bestinterest of the subject to do so.

Duration of treatment with compound 1: 84 days with up to 3 repeats ofthe 84-day cycle for a total period of up to 336 days.

Duration of follow up after end of treatment with study medicine: 4weeks.

The patient's condition will be evaluated by the Investigator at the endof the study and appropriate standard of care medical treatment will beprovided as needed.

Main Criteria for Inclusion

-   -   1. Biopsy-proven C3 GN based on a renal biopsy within 8 weeks        prior to screening;    -   2. eGFR≥25 mL/min/1.73 m² (by MDRD equation);    -   3. If having a partner of childbearing potential, must use        adequate contraception throughout the study and for at least 3        months after completion of dosing; Adequate contraception is        defined as resulting in a failure rate of less than 1% per year        (combined estrogen and progestogen [oral, intravaginal, or        transdermal], or progestogen-only hormonal contraception (oral,        injectable, or implantable), intra-uterine device, intra-uterine        hormone releasing system, bilateral tubal occlusion,        vasectomized partner, or sexual abstinence);    -   4. Willing and able to give written Informed Consent and to        comply with the requirements of the study protocol; and    -   5. Judged to be otherwise healthy by the Investigator, based on        medical history, physical examination, and clinical laboratory        assessments. Clinical laboratory values that are outside of        normal limits (other than those specified in the Exclusion        Criteria) and/or with other abnormal clinical findings that are        judged by the Investigator not to be of clinical significance,        may be allowed.

Main Criteria for Exclusion

-   -   1. Proteinuria >8 g/day (or >8 g/g creatinine);    -   2. Use of eculizumab within 26 weeks prior to dosing;    -   3. History or presence of any form of cancer within the 5 years        prior to screening, with the exception of excised basal cell or        squamous cell carcinoma of the skin, or carcinoma in situ such        as cervical or breast carcinoma in situ that has been excised or        resected completely and is without evidence of local recurrence        or metastasis;    -   4. Positive HBV, HCV, or HIV viral screening test;    -   5. Any infection requiring antibiotic treatment that has not        cleared prior to starting compound 1 treatment on Day 1;    -   6. WBC count less than 4000/μL, or neutrophil count less than        2000/μL, or lymphocyte count less than 1000/μL;    -   7. Hemoglobin less than 9 g/dL (or 5.56 mmol/L) at screening;    -   8. Evidence of hepatic disease; AST, ALT, alkaline phosphatase,        or bilirubin>3× the upper limit of normal;    -   9. Participated in any clinical study of an investigational        product within 30 days prior to screening or within 5 half-lives        after taking the last dose; and    -   10. History or presence of any medical condition or disease        which, in the opinion of the Investigator, may place the subject        at unacceptable risk for study participation.        Duration of Treatment and Observation

The patient will be screened within a period not to exceed 21 days priorto Day 1. The compound 1 treatment period is at least 84 days and up to336 days, and the patient will be followed for 4 weeks (28 days) afterdosing is stopped.

To the extent possible, any adverse events that are deemed studydrug-related and are ongoing at discharge will be followed-up toresolution or until a determination is made that the unresolved event isstable. The patient's condition will be evaluated by the Investigator atthe end of the study and appropriate standard of care medical treatmentwill be provided as needed.

Safety Assessments

Safety assessments include adverse events, physical examinationabnormalities, vital signs, and clinical laboratory tests (includingblood chemistry, hematology, and urinalysis).

Efficacy Assessments

Efficacy Assessments Include:

-   -   1. First morning urinary PCR;    -   2. eGFR by Modification of Diet in Renal Disease (MDRD) formula        based on serum creatinine;    -   3. Plasma and urine pharmacodynamic markers, e.g., MCP-1, C3a,        C5a, properdin, and sC5b-9;    -   4. Glomerular inflammation (e.g., crescents, inflammatory cell        infiltrate, endocapillary proliferation) and C3 deposition in a        follow-up renal biopsy sample;        Pharmacokinetic Assessments

Concentrations of compound 1 and possible metabolites will be determinedin plasma from 2-mL blood samples collected in EDTA tubes on Days 8, 15,29, 57, and 85. The date and time of the last dose of compound 1 priorto sample collection for compound 1 measurement will be recorded. Thesamples will be kept frozen at −70° C. or lower and shipped on dry icefor assay.

Plasma samples will continue to be collected every 4 weeks during anysubsequent 84-day cycles.

Pharmacodynamic Markers

Plasma samples will be collected on Day 1 (pre-dose), and Days 8, 15,29, 57, and 85 for pharmacodynamic marker measurements, including, forexample, complement fragments, and inflammatory cytokine and chemokinelevels. Urine samples will also be collected on Day 1 (pre-dose) andDays 8, 15, 29, 57, and 85 for biomarker assessments including, forexample, MCP-1, complement fragments, and inflammatory chemokine andcytokine levels.

Plasma and urine samples will continue to be collected every 4 weeksduring any subsequent 84-day cycles.

Renal Histology

Renal biopsies will be analyzed by periodic acid—Schiff (PAS) staining,immunofluorescence staining for C3, C5b-9, and potentially othermarkers. Electron microscopy may also be performed.

Statistical Methods

Demographics and Baseline Characteristics

All patient baseline characteristics and demographic data (age, sex,race, ethnicity, weight, height, body mass index, smoking status, viraltest results, C3 GN disease duration (from time of first diagnosis basedon renal biopsy), renal transplant history, eGFR, proteinuria (PCR),urinary MCP-1:creatinine ratio, physical examination abnormalities,medical history, previous (within 6 months of screening) and concomitantmedications (including other treatments for C3 GN) at study entry willbe listed.

Safety Analysis

The primary safety endpoint is the patient incidence of adverse events.

Other Safety Endpoints Include:

-   -   1. Change from baseline in all safety laboratory parameters;    -   2. Change from baseline in vital signs.

All clinical safety and tolerability data will be listed.Treatment-emergent adverse events will be listed by System Organ Class,by relatedness and by maximum severity. Serious adverse events andadverse events leading to withdrawal will be listed. Vital signs andchange from baseline in vital signs will be listed by study visit.Laboratory data (actual values and change from baseline) will be listedby study visit. Abnormal laboratory values will be flagged.

Efficacy Analysis

The primary efficacy endpoints are the change from baseline over thetreatment period in eGFR and first morning urinary PCR.

Other efficacy endpoints include:

-   -   1. The percent change from baseline in plasma and urinary        biomarkers, e.g., MCP-1, C3a, C5a, properdin, and sC5b-9;    -   2. Change from baseline to follow-up biopsy in glomerular        inflammation (crescents, inflammatory cell infiltrate, and        endocapillary proliferation), C3 deposits, and C5b-9 deposits.

Change and percent change in the efficacy parameters during the 4-weekfollow-up period will also be assessed to determine the off-treatmenteffect.

Pharmacokinetic Analysis

Plasma samples will be collected on Days 8, 15, 29, 57, and 85 todetermine the plasma concentrations of compound 1 (and metabolites).Plasma concentrations of compound 1 will be listed and plotted by studyvisit.

Example 2 A Randomized, Double-Blind, Placebo-Controlled Phase 2 Studyto Evaluate the Safety and Efficacy of Compound 1 in Patients with C3Glomerulopathy

Protocol of the Study Planned

Aim

The aim of this study is to evaluate the effect of compound 1 treatmenton renal disease activity in patients with complement 3 glomerulopathy(C3G). The intent is to slow down or improve renal disease with compound1 treatment in these patients.

Objectives

The primary objective is to evaluate the efficacy of compound 1 comparedto placebo based on histologic changes in C3G pathology from kidneybiopsies taken before and during treatment.

The secondary objectives of this study include assessment of:

-   -   1. The safety of compound 1 compared to placebo based on the        incidence of adverse events, changes in clinical laboratory        measurements, and vital signs;    -   2. Changes in laboratory parameters of renal disease including        estimated glomerular filtration rate (eGFR), proteinuria, and        urinary excretion of monocyte chemoattractant protein-1 (MCP-1)        with compound 1 compared to placebo;    -   3. Health-related quality-of-life changes based on Short Form-36        version 2 (SF-36 v2) and EuroQOL-5D-5L (EQ-5D-5L) with compound        1 compared to placebo;    -   4. Evaluation of the pharmacokinetic profile of compound 1 in        patients with C3 glomerulopathy.

Additionally, changes from baseline in markers of alternative complementpathway involvement, e.g., C3, C3d, C3c, C3adesArg, C5, C5a, C5b-9,C5adesArg, and other markers of inflammation, may be assessed inplasma/serum or urine over the course of the treatment period.

Methodology

This is a Phase 2 study to test the efficacy, safety, and tolerabilityof compound 1 in patients with C3G, including both C3GN and DDD.Eligible patients will be stratified based on two factors:

-   -   1. C3GN or DDD, and    -   2. Having received a kidney transplant or not, prior to        randomization.

Patients will then be randomized, 1:1, to receive 30 mg compound 1 twicedaily or matching placebo for 26 weeks in a double-blind,placebo-controlled manner. The 26-week double-blind period will befollowed by a 26-week period during which all patients will receivecompound 1 treatment.

Patients will be screened for enrollment based on biopsy proven C3glomerulopathy (i.e., ≥2-levels of magnitude greater staining of C3 thanany combination of IgG, IgM, IgA, and C1q) and evidence of inflammationbased on leukocyte infiltration and/or endocapillary proliferation.

The screening period will be up to 28 days. Screening procedures willinclude written informed consent, demographics, medical history,medication history, physical examination and vital signs, 12-lead ECG,serum pregnancy test for women of childbearing potential, serumchemistry (including serum creatinine), hematology, urinalysis, urinaryprotein:creatinine ratio (PCR), viral and TB screening. If a patient didnot have a renal biopsy in the past 12 weeks, a renal biopsy needs to bedone prior to dosing. Prior to starting study drug treatment, bloodsamples will be collected for the following measurements to create abaseline profile for all patients:

-   -   1. C3, C3 d, C3c, C3adesArg, and C4;    -   2. C3 nephritic factor;    -   3. C5, C5a, C5b-9, C5adesArg;    -   4. Serum complement Factor H and factor B;    -   5. Serum paraprotein detection;    -   6. Complement factor H related protein 5 (CFHR5) mutation.

Patients meeting inclusion criteria will start study drug treatment onDay 1. Patients will take compound 1 30 mg or matching placebo orallytwice daily. The treatment period is 52 weeks (364 days). The study drugwill be taken in the morning preferably with food and in the eveningpreferably with food, approximately 12 hours after the morning dose.Patients who receive placebo during the first 26 weeks, will receivecompound 1 in a blinded cross-over. After the 364-day treatment period,all patients will be followed for 8 weeks (56 days) without study drugtreatment.

At post-Day 1 study visits, blood and urine samples will be collectedfor safety, efficacy, and pharmacokinetic and biomarker measurements. Aserum pregnancy test for women of childbearing potential will be doneregularly during the 52-week treatment period and at the end of the8-week follow-up period. Physical examinations and vital signsassessments will be performed throughout the study. Health-relatedquality of life using the EQ-5D-5L and SF-36 v2 surveys will be assessedperiodically over the course of the study. Study drug will be dispensedand drug accountability will be done. Concomitant medication and adverseevent assessments will be made at every study visit. A follow-up renalbiopsy will be performed at the following time points:

-   -   1. After the 26-week placebo-controlled treatment period;    -   2. If a patient is withdrawn early from the study, and    -   3. After the 52-week treatment period.

If a patient is on other immunosuppressive treatment at the start ofdosing, the dose(s) of concomitant immunosuppressive treatment may notbe increased during the study. Treatment with these other drugs may bereduced or stopped during the study, if the patient's conditionjustifies it. No new treatments may be added during the study period(active treatment period or follow up), unless the patient's conditiondeteriorates to the extent that the investigator deems it in the bestinterest of the patient to do so. This will be considered a treatmentfailure.

Patients who experience deteriorating renal function based on anincrease in serum creatinine of at least 50% (confirmed by a repeatmeasurement after 2 weeks) which is otherwise not explained (e.g.,dehydration, new medication), or an increase in proteinuria of >3 g/gcreatinine from baseline or to a level >8 g/g (confirmed by a repeatmeasurement after 2 weeks) during the 52-week treatment period, willexit the treatment phase of the study and be treated at the discretionof their doctor. They will remain in the study for follow up and outcomerecording. These will be considered treatment failures.

For study centers where enrollment of adolescents (12 to 17 years old)is approved, compound 1 or placebo dosing will initially be given basedon the body weight at screening and the dose will be adjusted based oncompound 1 plasma levels as shown in the table below.

Only in 12 to 17 year old patients, blood samples will be takenpre-dosing and at Hours 0.5, 1, 2, 3, 4, and 6 after the first compound1 dose on Day 1 and plasma samples will be sent to the centrallaboratory for expeditious measurement of compound 1 and its metabolitein these patients. Dose adjustments will be made based on AUC₀₋₆ asshown in the table below. These AUC_(0.6) thresholds are based on themean compound 1 plasma exposure (525 ng·hr/mL) and one standarddeviation (174 ng·hr/mL) above or below the mean in adult patients fromPhase 2 study CL002_168 in AAV.

compound 1 Initial Plasma compound AUC₀₋₆ compound 1 1/placebo (ng ·hr/mL) Dose Body weight dose on Day 1 Adjustment <40 kg (88 lb) 10 mgtwice ≥351 None daily <351 Increase dose to 20 mg twice daily 40-55 kg(88-121 lb) 20 mg twice 351 to 699 None daily <351 Increase dose to 30mg twice daily >699 Decrease dose to 10 mg twice daily >55 kg (121 lb)30 mg twice ≤699 None daily >699 Decrease dose to 20 mg twice daily

Patients will visit the study center during Screening and on Day 1(baseline) and Weeks 1, 2, 4, 8, 12, 16, 20, 26, 32, 38, 44, 52, and 60.

Duration of double-blind treatment with compound 1 or placebo: 26 weeks.

Duration of treatment with compound 1 after the double-blind treatmentperiod: 26 weeks.

Duration of follow up after end of treatment with study medicine: 8weeks.

Patients will be discharged from the study when all the Week 60 visitprocedures have been completed. The patient's condition will beevaluated by the Investigator at the end of the clinical trial (Week 60)and appropriate standard of care medical treatment will be provided toall patients as needed.

Number of Patients

Approximately 44 male or female patients with C3 glomerulopathy will beenrolled in this study. Patients who drop out before the Week 26 visitmay be replaced.

Main Criteria for Inclusion

-   -   1. Biopsy-proven C3 glomerulopathy, either DDD or C3GN, with        2-levels of magnitude greater staining of C3 than any        combination of IgG, IgM, IgA, and C1q, and with evidence of        inflammation, based on leukocyte infiltration or endocapillary        proliferation, observed in a renal biopsy taken within 12 weeks        prior to screening or during screening; patients with a kidney        transplant are eligible for the study;    -   2. Plasma C5b-9 above the upper limit of the reference range of        the central laboratory;    -   3. Male or female patients, aged at least 18 years; where        approved, adolescents (12-17 year old) may be enrolled; female        patients of childbearing potential may participate if adequate        contraception is used during, and for at least the three months        after study completion; Male patients with partners of        childbearing potential may participate in the study if they had        a vasectomy at least 6 months prior to randomization or if        adequate contraception is used during, and for at least the        three months after study completion; Adequate contraception is        defined as resulting in a failure rate of less than 1% per year        (combined estrogen and progestogen [oral, intravaginal, or        transdermal], or progestogen-only hormonal contraception (oral,        injectable, or implantable), intra-uterine device, intra-uterine        hormone releasing system, bilateral tubal occlusion,        vasectomized partner, or sexual abstinence);    -   4. Willing and able to give written Informed Consent and to        comply with the requirements of the study protocol; written        Informed Consent should be obtained from the legal guardian in        accordance with regional laws or regulations for patients 12 to        17 years of age; and    -   5. Judged to be otherwise fit for the study by the Investigator,        based on medical history, physical examination, and clinical        laboratory assessments. Patients with clinical laboratory values        that are outside of normal limits (other than those specified in        the Exclusion Criteria) and/or with other abnormal clinical        findings that are judged by the Investigator not to be of        clinical significance, may be entered into the study.

Main Criteria for Exclusion

-   -   1. Pregnant or nursing;    -   2. Proteinuria >8 g/day (or >8 g/g creatinine);    -   3. More than 50% interstitial fibrosis on renal histology;    -   4. Use of eculizumab within 26 weeks prior to dosing;    -   5. Secondary C3 disease, e.g., infection-associated disease, or        associated with another systemic or autoimmune disease;    -   6. Currently on dialysis or likely will require dialysis within        7 days;    -   7. History or presence of any form of cancer within the 5 years        prior to screening, with the exception of excised basal cell or        squamous cell carcinoma of the skin, or carcinoma in situ such        as cervical or breast carcinoma in situ that has been excised or        resected completely and is without evidence of local recurrence        or metastasis;    -   8. Positive HBV, HCV, or HIV viral screening test;    -   9. Evidence of tuberculosis based on interferon γ release assay        (IGRA), tuberculin purified protein derivative (PPD) skin test,        or chest radiography done at screening or within 6 weeks prior        to screening;    -   10. WBC count less than 3500/uL, or neutrophil count less than        1500/uL, or lymphocyte count less than 800/uL before start of        dosing;    -   11. Evidence of hepatic disease; AST, ALT, alkaline phosphatase,        or bilirubin >3× the upper limit of normal before start of        dosing;    -   12. Known hypersensitivity to compound 1 or inactive        ingredients;    -   13. Participated in any clinical study of an investigational        product within 30 days prior to screening or within 5 half-lives        after taking the last dose; and    -   14. History or presence of any medical condition or disease        which, in the opinion of the Investigator, may place the patient        at unacceptable risk for study participation.        Duration of Treatment and Observation

Patients will be screened within a period not to exceed 28 days prior toDay 1. The treatment period is 52 weeks (364 days) and all patients willbe followed for 8 weeks (56 days) after the dosing period.

To the extent possible, any adverse events that are deemed studydrug-related and are ongoing at discharge will be followed-up toresolution or until a determination is made that the unresolved event isstable. The patient's condition will be evaluated by the Investigator atthe end of the clinical trial and appropriate standard of care medicaltreatment will be provided to all patients as needed.

Safety Assessments

Safety assessments include adverse events, physical examinationabnormalities, vital signs, and clinical laboratory tests (includingblood chemistry, hematology, and urinalysis).

Efficacy Assessments

Efficacy Assessments Include:

-   -   1. Renal histology to determine the C3G Histologic Index (CHI)        for disease activity and chronicity;    -   2. eGFR calculated by the Modification of Diet in Renal Disease        (MDRD) equation from serum creatinine;    -   3. First morning urinary PCR;    -   4. First morning urinary MCP-1:creatinine ratio;    -   5. EQ-5D-5L and SF-36 v2.        Pharmacokinetic Assessments

Concentrations of compound 1 and metabolites will be determined inplasma according to the Time and Events Table.

Pharmacodynamic Markers

Plasma/serum samples will be collected according to the Time and EventsTable for pharmacodynamic marker measurements, including, for example,complement fragments, and inflammatory cytokine and chemokine levels.Urine samples will also be collected according to the Time and EventsTable for biomarker assessments including, for example, complementfragments, sCD163, and inflammatory chemokine and cytokine levels.

Renal Histology

For eligibility assessment, renal biopsy samples will be assessed byimmunofluorescence staining for C3 and immunoglobulins. Patients musthave biopsy-proven C3 glomerulopathy, either DDD or C3GN, with ≥2-levelsof magnitude greater staining of C3 than any combination of IgG, IgM,IgA, and C1q, and with evidence of inflammation, based on leukocyteinfiltration or endocapillary proliferation, observed in a renal biopsytaken within 12 weeks prior to screening or during screening.

All renal biopsies will also be analyzed based on hematoxylin-eosin(H&E) staining, periodic acid-Schiff (PAS) staining, trichrome, andJones methenamine silver staining. These renal biopsies will beevaluated by a central reader, blinded to treatment assignment fromeither slides or high-resolution electronic images.

The central reader will determine the degree of disease activity andchronicity.

Statistical Methods

Demographics and Baseline Characteristics

All patient baseline characteristics and demographic data (age, sex,race, ethnicity, weight, height, body mass index, viral test results, C3glomerulopathy disease duration (from time of first diagnosis based onrenal biopsy), eGFR, proteinuria (PCR), complement marker levels,urinary MCP-1:creatinine ratio, physical examination abnormalities,medical history, previous (within 6 months of screening) and concomitantmedications (including other treatments for C3 glomerulopathy) at studyentry will be listed by study center and patient number, and will alsobe summarized.

Efficacy Analysis

The primary efficacy endpoint is the percent change from baseline toweek 26 in the C3G Histologic Index (CHI) for disease activity. Thecompound 1 and placebo groups will be compared by ANCOVA with treatmentgroup and randomization strata (C3GN or DDD, and renal transplant ornot) as factors, and baseline as covariate. Point estimates andcorresponding 95% confidence intervals will be estimated for thedifference between the compound 1 and placebo control group.

Since the placebo group will receive compound 1 during the second 26weeks of the study, the change from Week 26 to Week 52 in the CHI in theplacebo control group will be compared to the change from baseline toWeek 26 in this group. This analysis will be done by the paired t-test.Point estimates and corresponding 95% confidence intervals will beestimated for the difference between the second 26 weeks (compound 1treatment) and the first 26 weeks (placebo treatment).

The change from baseline to Week 52 in the CHI will also be compared tothe change from baseline with Week 26 in placebo control group usingsimilar methodology as described for the primary efficacy endpoint.

Other Efficacy Endpoints Include:

-   -   1. The percent change from baseline in the CHI for disease        chronicity over the placebo-controlled 26-week treatment period;    -   2. The change and percent change from baseline in eGFR over the        placebo-controlled 26-week treatment period;    -   3. The percent change from baseline in urinary PCR over the        placebo-controlled 26-week treatment period;    -   4. The percent change from baseline in urinary MCP-1:creatinine        ratio over the placebo-controlled 26-week treatment period;    -   5. Change from baseline in EQ-5D-5L and SF-36 v2 (domains and        component scores) over the placebo-controlled 26-week treatment        period.

Continuous variables, including eGFR, urinary PCR, urinaryMCP-1:creatinine ratio, EQ-5D-5L, and SF-36 v2 will be analyzed using amixed effects model for repeated measures (MMRM) with treatment group,visit, treatment-by-visit interaction, and randomization strata (C3GN orDDD, and renal transplant or not) as factors, and baseline as covariate.Patients will be considered as repeated measure units over visits. Pointestimates and corresponding 95% confidence intervals will be estimatedfor the difference between the compound 1 group and the control groupacross 26 weeks using simple contrast from the model. Similar to theprimary endpoint, the second 26 weeks will be compared to the first 26weeks for the placebo group.

Change and percent change in the efficacy parameters during the 8-weekfollow-up period will also be assessed to determine the off-treatmenteffect.

Change from baseline in markers of alternative complement pathwayactivation will be reported.

Summary statistics will be calculated for each of the efficacyendpoints. For continuous variables, numbers, means, medians, ranges,standard deviations, standard errors, and 95% confidence intervals willbe calculated. Geometric means will be calculated for urinary PCR andMCP-1:creatinine, and other measurements that are not normallydistributed.

Safety Analysis

Safety Endpoints Include:

-   -   1. Patient incidence of treatment-emergent serious adverse        events, adverse events, and withdrawals due to adverse events;    -   2. Change from baseline and shifts from baseline in all safety        laboratory parameters;    -   3. Change from baseline in vital signs.

All patients who are randomized and received at least one dose of studymedication will be included in the safety population.

All clinical safety and tolerability data will be listed by treatmentgroup and by patient, and will be summarized by treatment group.

All reported adverse events will be coded using MedDRA and listed bySystem Organ Class, preferred term, and verbatim term.

Treatment-emergent adverse events will be listed and summarized bytreatment group by System Organ Class, by relatedness and by maximumseverity.

Treatment-emergent serious adverse events and adverse events leading towithdrawal will be summarized by treatment group.

Individual vital signs and change from baseline in vital signs will belisted by treatment group, patient, and study visit, and summarized bytreatment group.

Laboratory data (actual values and change from baseline) will be listedby treatment group, patient, and study visit. Abnormal laboratory valueswill be flagged. Laboratory data will also be summarized by treatmentgroup and study visit. Shift tables will be generated for shifts inlaboratory parameters by study visit.

Pharmacokinetic and Pharmacodynamic Marker Analysis

Plasma samples will be collected over the course of the study todetermine the PK profile of compound 1 (and metabolites). Individualplasma concentrations of compound 1 (and metabolites) will be listed,plotted, and summarized descriptively and graphically. PK parameterswill be calculated based on plasma compound 1 concentrations at the timeof sample collection in relation to time of administration of the mostrecent dose of study medication. PK parameters of significantmetabolites may also be calculated.

Plasma and urinary PD markers will be summarized and may be analyzedusing methods analogous to the efficacy parameters. The followingparameters will be determined, where possible, in 12-17 year oldpatients:

-   -   Cmax Maximum plasma concentration    -   tmax Time of maximum plasma concentration    -   AUC₀₋₆ Area under the plasma concentration-time curve from Time        0 to Hour 6 on Day 1    -   Cmin Trough level plasma concentrations at post-Day 1 visits

The relationship between PK parameters and renal function based on eGFRwill be evaluated. The data may also be used to evaluate the PK/PDrelationship of compound 1 treatment. To this end, the change and/orpercent change from baseline in urinary PCR, eGFR, urinaryMCP-1:creatinine ratio, and other biomarkers may be used as PD markers.

What is claimed is:
 1. A method of treating a human suffering fromcomplement 3 glomerulopathy comprising administering to the human aneffective amount of a compound having the formula


2. The method of claim 1 wherein the human suffers from complement 3glomerulonephritis.
 3. The method of claim 1 wherein the human suffersfrom progressive complement 3 glomerulonephritis.
 4. The method of claim1 wherein the human suffers from recurrent complement 3glomerulonephritis after a renal transplant.
 5. The method of claim 1wherein the human suffers from dense deposit disease.
 6. The method ofclaim 1 wherein the complement 3 glomerulopathy is refractory to othertreatment.
 7. The method of claim 1 wherein the complement 3glomerulopathy is refractory to immunosuppressive drugs.
 8. The methodof claim 1 wherein the complement 3 glomerulopathy is refractory to oneor more of rituximab, cyclophosphamide, mycophenolate mofetil,tacrolimus, and steroids.
 9. The method of claim 1 wherein the compoundis administered twice daily.
 10. The method of claim 1 wherein thecompound is administered once a day.
 11. The method of claim 1 whereinthe compound is administered orally.
 12. The method of claim 1 whereinthe human receives 30 mg of the compound twice daily.
 13. The method ofclaim 1, wherein the human has a Complement factor H related protein 5(CFHR5) mutation.